CA3093802A1 - Substituted imidazopyridines as inhibitors of plasma kallikrein and uses thereof - Google Patents

Substituted imidazopyridines as inhibitors of plasma kallikrein and uses thereof Download PDF

Info

Publication number
CA3093802A1
CA3093802A1 CA3093802A CA3093802A CA3093802A1 CA 3093802 A1 CA3093802 A1 CA 3093802A1 CA 3093802 A CA3093802 A CA 3093802A CA 3093802 A CA3093802 A CA 3093802A CA 3093802 A1 CA3093802 A1 CA 3093802A1
Authority
CA
Canada
Prior art keywords
nitrogen
oxygen
sulfur
methyl
heteroatoms selected
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CA3093802A
Other languages
French (fr)
Inventor
Nikolaos PAPAIOANNOU
Sarah Jocelyn FINK
Thomas Allen MILLER
Gerald Wayne SHIPPS, Jr.
Jeremy Mark Travins
David Edward EHMANN
Alastair Rae
John Mark Ellard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
Original Assignee
Shire Human Genetics Therapies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shire Human Genetics Therapies Inc filed Critical Shire Human Genetics Therapies Inc
Publication of CA3093802A1 publication Critical patent/CA3093802A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The present invention provides compounds and compositions thereof which are useful as inhibitors of plasma kallikrein and which exhibit desirable characteristics for the same.

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME:
ii NOTE POUR LE TOME / VOLUME NOTE:

SUBSTITUTED IMIDAZOPYRIDINES AS INHIBITORS OF PLASMA KALLIKREIN AND USES
THEREOF
I. BACKGROUND OF THE INVENTION
[0001] Plasma Kallikrein (pKal) is a serine protease zymogen in blood that is converted to its catalytically active form by coagulation factor XIIa, and contributes to the innate inflammatory response and intrinsic cascade of blood coagulation. The mechanisms that lead to the activation of this pathway in vivo include interactions with polyphosphates released from activated platelets and deficiency of Cl inhibitor (Cl-INH), the primary physiological inhibitor of pKal. pKal-mediated cleavage of high-molecular weight kininogen generates the potent vasodilator and pro-inflammatory nonapeptide bradykinin (BK), which activates the bradykinin
2 receptor. Subsequent cleavage of BK by carboxypeptidases generates des-Arg9-BK, which activates the B1 receptor. Both B1 and B2 receptors are expressed by vascular, glial, and neuronal cell types, with the highest levels of retinal expression detected in the ganglion cell layer and inner and outer nuclear layers. Activation of B1 and B2 receptors causes vasodilation and increases vascular permeability.
[0002] pKal is also associated with a number of disorders, such as hereditary angioedema (HAE), an autosomal dominant disease characterized by painful, unpredictable, recurrent attacks of inflammation affecting the hands, feet, face, abdomen, urogenital tract, and the larynx.
Prevalence for HAE is uncertain but is estimated to be approximately 1 case per 50,000 persons without known differences among ethnic groups. HAE is caused by deficient (Type I) or dysfunctional (Type II) levels of C1-INH, which inhibits pKal, bradykinin, and other serine proteases in the blood. Individuals with hereditary angioedema (HAE) are deficient in Cl-INH
and consequently undergo excessive bradykinin generation, which in turn cause painful, debilitating, and potentially fatal swelling attacks. If left untreated, HAE
can result in a mortality rate as high as 40% primarily due to upper airway obstruction.
SUMMARY OF THE INVENTION
[0003] The present disclosure is based on, at least in part, the development of a number of compounds which bind to plasma kallikrein and effectively inhibit its activity. Accordingly, provided herein are compounds and uses thereof for targeting pKal and/or treating pKal-mediated diseases and disorders.
[0004] In some embodiments, the present invention provides a compound of Formula (I):

R

NI/
R7 \
N N (I) R6 c,B
R3 L j or a pharmaceutically acceptable salt thereof, wherein each of Cy A, cyu, L, R2, R3, R4, R5, R6, R7, le, and R9 is defined and described in classes and subclasses herein.
In certain embodiments, the present invention provides compounds of Formulae (I)-(V), as defined and described in classes and subclasses herein.
[0005] In some embodiments, the present invention also provides methods of using compounds of Formulae (I)-(V).
III. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
A. Definitions
[0006] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein.
As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS
version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B.
and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[0007] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.
[0008] The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocyclyl," "cycloaliphatic"
or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
In some embodiments, "cycloaliphatic" (or "carbocycly1" or "cycloalkyl") refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0009] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon;
the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrroly1), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
[0010] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.
[0011] The term "alkylene" refers to a bivalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2)-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
[0012] The term "halogen" means F, Cl, Br, or I.
[0013] The term "aryl" refers to monocyclic and bicyclic ring systems having a total of five to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In some embodiments, an 8-10 membered bicyclic aryl group is an optionally substituted naphthyl ring. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term "aryl," as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
[0014] The terms "heteroaryl" and "heteroar-" refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 7C electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring,"
"heteroaryl group,"
or "heteroaromatic," any of which terms include rings that are optionally substituted.
[0015] As used herein, the terms "heterocyclyl," "heterocyclic radical,"
and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in this context in reference to a ring atom, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N
(as in 3,4-dihydro-2H-pyrroly1), NH (as in pyrrolidinyl), or +NR (as in N-substituted pyrrolidinyl).
[0016] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical," are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic.
The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
[0017] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated"
is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
[0018] As used herein and unless otherwise specified, the suffix "-ene"
is used to describe a bivalent group. Thus, any of the terms above can be modified with the suffix "-ene" to describe a bivalent version of that moiety. For example, a bivalent carbocycle is "carbocycylene", a bivalent aryl ring is "arylene", a bivalent benzene ring is "phenylene", a bivalent heterocycle is "heterocyclylene", a bivalent heteroaryl ring is "heteroarylene", a bivalent alkyl chain is "alkylene", a bivalent alkenyl chain is "alkenylene", a bivalent alkynyl chain is "alkynylene", and so forth.
[0019] As described herein, compounds of the invention may, when specified, contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted"
group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
[0020] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH2)0_4R ; -(CH2)0.40R ; -0(CH2)0.4R , -0(CH2)0.4C(0)0R ; -0(CH2)0_401V; -(CH2)0_4CH(OR )2; -(CH2)0-4SIV; -(CH2)0_4Ph, which may be substituted with R ; -(CH2)0.40(CH2)04Ph which may be substituted with R ; -CH=CHPh, which may be substituted with R ; -(CH2)0.40(CH2)04-pyridyl which may be substituted with R ;
-NO2; -CN; -N3; -(CH2)0-4N(R )2; -(CH2)0-4N(R )C(0)R ; -N(R )C(S)R ; -(CH2)0-4N(R )C(0)NR 2; -N(R )C(S)NR 2; -(CH2)0.4N(R )C(0)0R ; -N(R )N(R )C(0)R ; -N(R )N(R )C(0)NR 2; -N(R )N(R )C(0)0R ; -(CH2)0.4C(0)R ; -C(S)R ; -(CH2)0.4C(0)0R ; -(CH2)0.4C(0)SR ; - (CH2)0.4C(0)0SiR 3; -(CH2)0.40C(0)R ; -0C(0)(CH2)0.45R , -SC(S)SR ; -(CH2)0.45C(0)R ; -(CH2)0.4C(0)NR 2; -C(S)NR 2; -C(S)SR ; -SC(S)SR , -(CH2)0.40C(0)NR 2;
-C(0)N(OR )R ; -C(0)C(0)R ; -C(0)CH2C(0)R ; -C(NOR )R ; -(CH2)0_4SSR ; -(CH2)0-45(0)2R ; -(CH2)0.4S(0)20R ; -(CH2)0_40S(0)2R ; -S(0)2NR 2; - (CH2)0_4S(0)R ; -N(R )S(0)2NR 2; -N(R )S(0)2R ; -N(OR )R ; -C(NH)NR 2; -P(0)2R ; -P(0)R 2; -0P(0)R 2; -0P(0)(OR )2; SiR 3; -(C14 straight or branched alkylene)O-N(R )2; or -(C1_4 straight or branched alkylene)C(0)0-N(R )2, wherein each R may be substituted as defined below and is independently hydrogen, C1.6 aliphatic, -CH2Ph, -0(CH2)0413h, -CH2-(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R , taken together with their intervening atom(s), form a 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
[0021] Suitable monovalent substituents on R (or the ring formed by taking two independent occurrences of R together with their intervening atoms), are independently halogen, -(CH2)0.21e, -(haloR'), -(CH2)0-20H, -(CH2)0-20R., -(CH2)0.2CH(OR')2;
-0(haloR.), -CN, -N3, -(CH2)0.2C(0)R., -(CH2)0.2C(0)0H, -(CH2)0.2C(0)01e, -(CH2)0.25le, -(CH2)0_25H, -(CH2)0.2NH2, -(CH2)0.2NHR", -(CH2)0_2NR"2, -NO2, -C(0)SR', -(C1_4 straight or branched alkylene)C(0)01e, or -SSR. wherein each It' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from Ci.
4 aliphatic, -CH2Ph, -0(CH2)0.11311, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R include =0 and =S.
[0022] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR*2, =NNHC(0)R*, =NNHC(0)0R*, =NNHS(0)2R*, =NR*, =NOR*, -0(C(R*2))2-30-, or -S(C(R*2))2-35-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted" group include: -0(CR*2)2.30-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0023] Suitable substituents on the aliphatic group of R* include halogen, -It', - (halole), -OH, -OR', -0(halole), -CN, -C(0)0H, -C(0)01e, -NH2, -NEIR', -NR'2, or -NO2, wherein each It' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C1_4 aliphatic, -CH2Ph, -0(CH2)0413h, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0024] Suitable substituents on a substitutable nitrogen of an "optionally substituted"
group include -le, NIRt2,-C(0)1e, -C(0)01e, -C(0)C(0)1e, -C(0)CH2C(0)1e, -S(0)21e, -S(0)2NR1.2, -C(S)NR1.2, -C(NH)NR1.2, or -N(le)S(0)2Rt; wherein each Ie is independently hydrogen, C1.6 aliphatic which may be substituted as defined below, unsubstituted -0Ph, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of le, taken together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0025] Suitable substituents on the aliphatic group of le are independently halogen, -le, - (halole), -OH, -OR', -0(halole), -CN, -C(0)0H, -C(0)01e, -NH2, -NEIR', -Nle2, or -NO2, wherein each le is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci.4 aliphatic, -CH2Ph, -0(CH2)0413h, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0026] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
[0027] In certain embodiments, the neutral forms of the compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. In some embodiments, the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
[0028] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the
29 PCT/US2019/021897 structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a '3C- or '4C-enriched carbon are within the scope of this invention.
Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
[0029] The term "oxo," as used herein, means an oxygen that is double bonded to a carbon atom, thereby forming a carbonyl.
[0030] The symbol "_", except when used as a bond to depict unknown or mixed stereochemistry, denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.
[0031] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.
[0032] A "dosing regimen" (or "therapeutic regimen"), as that term is used herein, is a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
[0033] As will be understood from context, a "reference" sample or subject is one that is sufficiently similar to a particular sample or subject of interest to permit a relevant comparison.
In some embodiments, information about a reference sample is obtained simultaneously with information about a particular sample. In some embodiments, information about a reference sample is historical. In some embodiments, information about a reference sample is stored, for example in a computer-readable medium. In some embodiments, comparison of a particular sample of interest with a reference sample establishes identity with, similarity to, or difference of the particular sample of interest relative to the reference.
[0034] As used herein, the term "sample" refers to a biological sample obtained or derived from a source of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood, e.g., whole blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum;
saliva; urine;
cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph;
gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and/or excretions; and/or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from a subject. In some embodiments, obtained cells are or include cells from a subject from whom the sample is obtained. In some embodiments, a sample is a "primary sample" obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood (e.g., whole blood), lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term "sample" refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample.
For example, filtering using a semi-permeable membrane. Such a "processed sample" may comprise, for example nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc.
[0035] As used herein, the phrase "therapeutic agent" refers to any agent that has a therapeutic effect and/or elicits a desired biological and/or pharmacological effect, when administered to a subject.
[0036] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent that confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). In particular, the "therapeutically effective amount" refers to an amount of a therapeutic agent effective to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventative effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease, and/or also lessening the severity or frequency of symptoms of the disease. A therapeutically effective amount is commonly administered in a dosing regimen that may comprise multiple unit doses. For any particular therapeutic agent, a therapeutically effective amount (and/or an appropriate unit dose within an effective dosing regimen) may vary, for example, depending on route of administration, on combination with other pharmaceutical agents. Also, the specific therapeutically effective amount (and/or unit dose) for any particular subject may depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific therapeutic agent employed; the specific composition employed;
the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and/or rate of excretion or metabolism of the specific therapeutic agent employed; the duration of the treatment; and like factors as is well known in the medical arts.
[0037] As used herein, the term "treatment" (also "treat" or "treating") refers to any administration of a substance (e.g., provided compositions) that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition. Such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and/or condition.

B. Compounds
[0038] In some embodiments, a provided compound is of Formula (I):

R

N
R7 \
N N (I) R CyA CvB

or a pharmaceutically acceptable salt thereof, wherein:
CyA is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyA
is substituted with 0-4 RA groups;
each RA is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from Ci.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
CyB is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-RB groups;
each RB is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
L is selected from -QC(R)2-, -C(R)2Q-, -QC(Q)-, -C(Q)Q-, -C(R)2QC(0)-, and -C(0)QC(R)2-, wherein each Q is independently a monovalent or divalent group as valency allows, selected from the group consisting of 0, N(R), or (S);
RI-, R2, R3, and R4 are independently selected from hydrogen and C1-6 aliphatic;
R5, R6, R7, R8, and R9 are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;

or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur;
with the proviso that the compound is other than N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-243-chloroquinolin-6-yl)methyl)isonicotinamide.
[0039] In some embodiments, a provided compound, or a pharmaceutically acceptable salt thereof, has a structure of Formula (I), with the proviso that CyA is a group other than pyridinediyl and the compound is other than N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-y1)methyl)isonicotinamide.
[0040] In some embodiments, CyA is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyA is substituted with 0-4 RA groups.
[0041] In some embodiments, CyA is selected from 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur wherein CyA is substituted with 0-4 RA groups.
[0042] In some embodiments, CyA is a 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
[0043] In some embodiments, CyA is a 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyA is substituted with 0-3 RA
groups. In some embodiments, CyA is a 6-membered heteroarylene having 1 nitrogen, wherein CyA is substituted with 0-3 RA groups. In some embodiments, CyA is pyridinediyl. In some embodiments, CyA is selected from either:

(RA)o-3 (RA)o-3 I AN
or wherein * represents to point of attachment to L.
[0044] In some embodiments, CyA is a 5-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyA is substituted with 0-2 RA
groups. In some embodiments, CyA is a pyrrolediyl substituted with 0-3 RA
groups. In some embodiments, CyA is a pyrazolediyl substituted with 0-2 RA groups. In some embodiments, CyA
is a triazolediyl substituted with 0-1 RA groups. In some embodiments, CyA is a thiazolediyl substituted with 0-1 RA groups. In some embodiments, CyA is an unsubstituted tetrazolediyl. In some embodiments, CyA is an unsubstituted oxadiazolediyl. In some embodiments, CyA is an unsubstituted thiadiazolediyl. In some embodiments, CyA is an imidazolediyl substituted with 0-2 RA groups. In some embodiments, CyA is a oxazolediyl substituted with 0-1 RA
groups. In some embodiments, CyA is a isoxazolediyl substituted with 0-1 RA groups.
[0045] In some embodiments, CyA is a 7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur wherein CyA is substituted with 0-4 RA
groups. In some embodiments, CyA is a 9-membered bicyclic heteroarylene having heteroatoms selected from oxygen, nitrogen, or sulfur wherein CyA is substituted with 0-4 RA
groups. In some embodiments, CyA is a 9-membered bicyclic heteroarylene having 2 nitrogens wherein CyA is substituted with 0-4 RA groups. In some embodiments, CyA is a pyrrolopyridinediyl substituted with 0-4 RA groups.
[0046] In some embodiments, CyA is selected from the group consisting of:
* (RA)0-3 NI/ \
JR N=N, N---1 (R )0-1 N--I N--I
-N
(R )o-2 jN-N N-N SH \( --1 N:=-\ N-NH N7-=\
N H (RA()_ õ\.(1'''µ A
(R )0-2 (RA)o_i (RA)o-i \(NH
õ N
NI \
vc...N\H*
NI*
(RA
-N V(RA)o-i (RA)o-4 N-NH A, 0 H*(R ,N-4* (RA)0_1 s, v -N V -N
(RA)0-2 (RA * H*
V -N
wherein * represents to point of attachment to L.
[0047] In some embodiments, each RA is independently selected from an optionally substituted group selected from C1.6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
[0048] In some embodiments, substituents on an optionally substituted RA
group are independently halogen, (CH2)0-41V, -(CH2)0_401V; and -(CH2)0.4C(0)0R , wherein each R is independently hydrogen, C 1.6 aliphatic, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0049] In some embodiments, a single instance of RA is C1-6 aliphatic substituted with halogen.
[0050] In some embodiments, a single instance of RA is C1-6 aliphatic substituted with -(CH2)0_40R , wherein R is hydrogen or C1-6 aliphatic.
[0051] In some embodiments, a single instance of RA is C1-6 aliphatic substituted with -(CH2)0.4C(0)0R , wherein R is hydrogen or C1-6 aliphatic.
[0052] In some embodiments, a single instance of RA is C1-6 aliphatic is substituted with 5-6 membered saturated, partially unsaturated, or aryl ring haying 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0053] In some embodiments, a single instance of RA is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, a single instance of RA is optionally substituted cyclopropyl. In some embodiments, a single instance of RA is cyclopropyl substituted with -(CH2)0.4C(0)0R and R is hydrogen or C1-6 aliphatic.
[0054] In some embodiments, CyB is selected from phenyl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl haying 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroaryl haying 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-5 RB
groups. In some embodiments, CyB is selected from phenyl and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-5 RB
groups.
[0055] In some embodiments, CyB is a 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-5 RB
groups.
[0056] In some embodiments, CyB is a 9-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-5 RB
groups. In some embodiments, CyB is a 9-membered bicyclic heteroaryl haying 2-3 nitrogens, wherein CyB is substituted with 0-5 RB groups. In some embodiments, CyB is an imidazopyridinyl group substituted with 0-5 RB groups. In some embodiments, CyB is a pyrazolopyridinyl group substituted with 0-5 RB groups. In some embodiments, CyB is a pyrrolopyridinyl group substituted with 0-4 RB groups. In some embodiments, CyB is a triazolopyridinyl group substituted with 0-4 RB groups. In some embodiments, CyB is an imidazopyrimidinyl group substituted with 0-4 RB groups. In some embodiments, CyB is a imidazopyridazinyl group substituted with 0-4 RB groups. In some embodiments, CyB is a indolizinyl group substituted with 0-5 RB groups. In some embodiments, CyB is a pyrazolopyrimidinyl group substituted with 0-4 RB groups.
[0057] In some embodiments, CyB is a indolyl group substituted with 0-5 RB groups. In some embodiments, CyB is a benzofuranyl group substituted with 0-5 RB groups.
In some embodiments, CyB is a pyrazolopyrimidinyl group substituted with 0-4 RB
groups. In some embodiments, CyB is a benzimidazolyl group substituted with 0-4 RB groups. In some embodiments, CyB is a thienopyridinyl group substituted with 0-4 RB groups.
[0058] In some embodiments, CyB is selected from the group consisting of:
N i \\ HN N 1 N N N
\ N N,N
t It I \Op t It t l H
N N ' _.,\e NiN
(RB)0-5 (RB)0-5 (RB)0-4 (RB)0-4 (RB)0-4 (RB)0-4 I NjN
(RB)o-5 (RB)o-4 ''''=-:"-N =N

410 b N N I
(RB)o-5 (RB)o-5 (RB)o-4 (RB)o-4 (RB)o-4 =
[0059] In some embodiments, CyB is a 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-5 RB

groups. In some embodiments, CyB is a 10-membered bicyclic heteroaryl having 1 nitrogen, wherein CyB is substituted with 0-5 RB groups. In some embodiments, CyB is a quinolonyl group substituted with 0-5 RB groups. In some embodiments, CyB is a quinoxalinyl group substituted with 0-5 RB groups. In some embodiments, CyB is selected from the group consisting of:
N
(RB)0_5 Nr----)(RB)0_5 =
[0060] In some embodiements, each RB is independently selected from halogen, -CN, -C(0)R, -C(0)2R, -N(R)2, -OR, or an optionally substituted group selected from C1-6 aliphatic, 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein each R is independently hydrogen or C1.6 aliphatic.
[0061] In some embodiments, substituents on an optionally substituted RB
group are independently selected from halogen, -(CH2)0_40R , -0(CH2)0_40R , -(CH2)0.4C(0)0R , and -(CH2)0.4N(R )2 wherein each R is independently hydrogen, C1.6 aliphatic, or two independent occurrences of R , taken together with their intervening atom(s), form an optionally substituted 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be further substituted.
[0062] In some embodiments, a single instance of RB is halogen. In some embodiments, a single instance of RB is -CN. In some embodiments, a single instance of RB is -C(0)R, wherein R
hydrogen or C1.6 aliphatic. In some embodiments, a single instance of RB is -C(0)2R, wherein R
hydrogen or C1.6 aliphatic. In some embodiments, a single instance of RB is -N(R)2, wherein R
hydrogen or C1.6 aliphatic. In some embodiments, a single instance of RB is -OR, wherein R
hydrogen or C1-6 aliphatic.
[0063] In some embodiments, a single instance of RB is C1-6 aliphatic substituted with -(CH2)0_40R , wherein R is hydrogen or C1-6 aliphatic.
[0064] In some embodiments, a single instance of RB is C1-6 aliphatic substituted with -0(CH2)0.40R , wherein R is hydrogen or C1-6 aliphatic.
[0065] In some embodiments, a single instance of RB is Ci.6 aliphatic substituted with -(CH2)0.4C(0)0R , wherein R is hydrogen or C1-6 aliphatic.
[0066] In some embodiments, a single instance of RB is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, a single instance of RB is optionally substituted cyclopropyl. In some embodiments, a single instance of RB is cyclopropyl is substituted with -(CH2)0_40R and R is hydrogen or C1.
6 aliphatic. In some embodiments, a single instance of RB is cyclopropyl is substituted with -(CH2)0.4C(0)0R and R is hydrogen or C1-6 aliphatic.
[0067] In some embodiments, a single instance of RB is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiements, a single instance of RB is optionally substituted 4-membered saturated monocyclic heterocyclyl having 1 oxygen. In some embodiements, a single instance of RB is 4-membered saturated monocyclic heterocyclyl having 1 oxygen, and substituted with -(CH2)0.40R , wherein R is hydrogen or C1.6 aliphatic.
[0068] In some embodiments, a single instance of RB is C1-6 aliphatic is substituted with -(CH2)0_4N(R )2, wherein two independent occurrences of R , taken together with their intervening atom(s), form an optionally substituted 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be further substituted. In some embodiments, a single instance of RB is C1.6 aliphatic substituted with -(CH2)04N(R )2, wherein two independent occurrences of R , taken together with their intervening atom(s), form an optionally substituted 5-membered saturated monocyclic ring further substituted with =0.
[0069] In some embodiments, L is selected from -QC(R)2-, -C(R)2Q-, -C(Q)Q-, or -C(R)2QC(0)-, wherein Q is independently a monovalent or divalent group as valency allows, selected from 0, N(R), or (S). In some embodiments, L is selected from -QC(R)2-, -C(R)2Q-, -C(Q)Q-, or -C(R)2QC(0)-, wherein Q is independently a monovalent or divalent group as valency allows, selected from 0 or N(R). In some embodiments, L is selected from the group consisting of:
õNyµtt ,õ,(Ntt \(O5\# /J\#0 NR 0 0 0 N N IsAN,(0 tAsc N
wherein # represents to point of attachment to CyA.
In some embodiments, L is -N(H)C(0)-. In some embodiments, L is -C(0)N(H)-.
[0070] In some embodiments, R5, R6, R7, le, and R9 are independently selected from hydrogen, halogen, -CN, -N(R)2, -OR, or an optionally substituted group selected from C1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, wherein each R is independently hydrogen or Ci.6 aliphatic. In some embodiments, R5, R8, and R9 are hydrogen.
[0071] In some embodiments, R6 is selected from hydrogen or halogen. In some embodiments, R6 is hydrogen. In some embodiments R6 is halogen. In some embodiments R6 is F. In some embodiments R6 is Cl. In some embodiments R6 is Br. In some embodiments R6 is I.
[0072] In some embodiments, R7 is selected from halogen or an optionally substituted C1-6 aliphatic. In some embodiments R7 is halogen. In some embodiments R7 is F. In some embodiments R7 is Cl. In some embodiments R7 is Br. In some embodiments R7 is I. In some embodiments, R7 is optionally substituted Ci.6 aliphatic. In some embodiments, R7 is optionally substituted C1-5 aliphatic. In some embodiments, R7 is optionally substituted C1-4 aliphatic. In some embodiments, R7 is optionally substituted C1-3 aliphatic. In some embodiments, R7 is optionally substituted C1-2 aliphatic. In some embodiments, R7 is alkynyl.
[0073] In some embodiments, a provided compound is of Formula (II):

N
CyA CyB
(II) R2 Ri or a pharmaceutically acceptable salt thereof, wherein each of CyA, cyB, R1, R2, R6, and R7 is defined and described in classes and subclasses herein;
with the proviso that the compound is other than N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-243-chloroquinolin-6-y1)methyl)isonicotinamide.
[0074] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of Formula (II), embodiments of variables CyA, cyB, R1, R2, -6, and R7 as defined above and described in classes and subclasses herein, also apply to compounds of Formula (II), both singly and in combination.
[0075] In some embodiments, a provided compound, or a pharmaceutically acceptable salt thereof, has a structure of Formula (II), with the proviso that CyA is a group other than pyridinediyl and the compound is other than N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6 yl)methyl)isonicotinamide.
[0076] In some embodiments, a provided compound, or a pharmaceutically acceptable salt thereof, has a structure of Formula (III-a), Formula (III-b), Formula (III-c), Formula (III-d), N
NH

N, OtN
(RA)0-1 )(CYB
(100-1 \CYB

(III-a) (III-b) rN

A--N'N N, OcyB N-N\ _cys R2 RI R,, (III-c) (III-d) wherein each of RA, CyB, R1, R2, R6, and R7 is defined and described in classes and subclasses herein.
[0077] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of Formula (III), embodiments of variables RA, CyB, R1, R2, R6, and R7 as defined above and described in classes and subclasses herein, also apply to compounds of Formula (III-a), Formula (III-b), Formula (III-c), and Formula (III-d) both singly and in combination.
[0078] In some embodiments of Formulae (I), (II), (III-a), (III-b), (III-c), and (III-d), CyB
is RI
RI2 w3 RIO

wherein:
wl, w2, -3, W and W4 are independently selected from carbon and nitrogen;
Rlo, RH, R12, K-13, and R14 are each optionally present when attached to a carbon atom, and if present correspond to an occurrence of RB independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
[0079] In some embodiments, Wl is nitrogen and W2, W3 and W4 are carbon.
In some embodiments, W2 is nitrogen and Wl, W3 and W4 are carbon. In some embodiments, W2 and W3 are nitrogen and Wl and W4 are carbon. In some embodiments, W2 and W4 are nitrogen and Wl and W3 are carbon.
[0080] In some embodiments of Formulae (I), (II), (III-a), (III-b), (III-c), and (III-d), CyB
is RI2 w3 I

R
wherein:
W2 is selected from carbon, nitrogen, oxygen, and sulfur;
W3, and W4 are independently selected from carbon and nitrogen;
R10, R11, R12, K-13, and R14 are each optionally present when attached to a carbon atom, and if present correspond to an occurrence of RB independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
[0081] In some embodiments, a provided compound is of Formula (IV):

IV

R"
L¨ CyA
w4R13 or a pharmaceutically acceptable salt thereof, wherein:

CyA is a 5-membered heteroarylene having 1-4 heteroatoms selected from oxygen or nitrogen, wherein CyA is substituted with 0-3 RA groups;
each RA is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from Ci.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
L is selected from -NC(0)- and -C(0)N-;
R6, le, and le are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
R7 is -F, -Cl, or -Br;
W4 is carbon or nitrogen;
Rm and R" are each optionally present, and if present are independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;

R13 is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C2-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
K is optionally present, and if present and is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C3-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
[0082] In some embodiments, CyA is a 5-membered heteroarylene having 1-4 heteroatoms selected from oxygen or nitrogen. In some embodiments, CyA is a 5-membered heteroarylene having 1-4 nitrogens. In some embodiments, CyA is a 5-membered heteroarylene having 1-4 nitrogens, wherein when CyA comprises 3 nitrogens, it is not a a 1,2,4-triazolediyl. In some embodiments, CyA is a 5-membered heteroarylene having 1-3 nitrogens. In some embodiments, CyA is a 5-membered heteroarylene having 1-2 nitrogens. In some embodiments, CyA is a 5-membered heteroarylene having 1 nitrogen. In some embodiments, CyA
is a 5-membered heteroarylene having 2 nitrogens. In some embodiments, CyA is a 5-membered heteroarylene having 3 nitrogens. In some embodiments, CyA is a 5-membered heteroarylene having 4 nitrogens.
[0083] In some embodiments, CyA is selected from the group consisting of:
Ni(CN--/
_Ns *vc/N---/
\(1\12N--1 wherein * represents to point of attachment to L.
[0084] In some embodiments, W4 is carbon. In some embodiments W4 is nitrogen.
[0085] In some embodiments, R" is optionally present, and if present is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
[0086] In some embodiments, R" is selected from -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
[0087] In some embodiments, IC is selected from halogen, optionally substituted C1-6 aliphatic, and optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl.
[0088] In some embodiments, IC is halogen. In some embodiments, le3 is -F. In some embodiments, R13 is -Cl. In some embodiments, R13 is -Br. In some embodiments, R13 is -I.
[0089] In some embodiments, R13 is optionally substituted Ci.6 aliphatic.
In some embodiments, R13 is optionally substituted C1-5 aliphatic. In some embodiments, R13 is optionally substituted C1-4 aliphatic. In some embodiments, R13 is optionally substituted C1-3 aliphatic. In some embodiments, R13 is optionally substituted C1-2 aliphatic.
[0090] In some embodiments, R13 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R13 is an optionally substituted 3- or 5-7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R13 is an optionally substituted 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R13 is an optionally substituted 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R13 is an optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R13 is an optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R13 is an optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R13 is an optionally substituted cyclopropyl.
[0091] In some embodiments, a provided compound is of Formula (V):

N
R6 \ V
R"
L¨CyA

or a pharmaceutically acceptable salt thereof, wherein:
CyA is a 5-membered heteroarylene having 1-4 nitrogens, wherein when CyA
comprises 3 N-NH
nitrogens, it is not L is selected from -NC(0)- and -C(0)N-;
R6, le, and le are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
R7 is -F, -Cl, or -Br;

K is optionally present, and if present is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;

K is optionally present, and if present is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
R13 is selected from -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -OC(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- or 5-7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;

K
is optionally present, and if present and is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C3.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
[0092]
In some embodiments, a provided compound is selected from the group consisting of N-((7-chloroimidazo[ 1,5 -a]pyridin-1 -yl)methyl)- 1-((3 -chloroquinolin-6-yl)methyl)- 1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-243-chloroquinolin-6-y1)methyl)isonicotinamide, 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-methylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide, N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropy141,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, 1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-isopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-145-methylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1H-pyrazole-4-carboxamide, 147-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N46-methoxyimidazo[1,2-a]pyridin-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-7-methylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-7-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-(trifluoromethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-145-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, 1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide, 1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide, N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-147-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-145,6-dimethylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, 1-((5-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide, 146-bromo-methylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide, N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxamide, N47,8-dichloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, 1-((6-chloro-5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methyl)-146-methylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, 146-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide, 146-bromo-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-246-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)thiazole-5-carboxamide, 1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide, 1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-147-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)- 1 -((7-(2-methylprop- 1-en-1 -yl)imidazo[1,2-a]pyridin-2-yl)methyl)- 1H-pyrazole-4-carboxamide, N((7-chloroimidazo[ 1,5 -a]pyridin- 1 -yl)methyl)-1 4(642-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, 14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-iodoimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-ethylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, (Z)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(prop-1-en-1-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-cyclopropylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-546-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide, N-((6-aminoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyanoimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-145-cyanoimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-145-cyclopropylpyrazolo[1,5-a]pyridin-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((5-amino-7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-methylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclobutylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-145-(hydroxymethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-methoxyimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, methyl 3 -(44(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3 -yl)propanoate, cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-ethynylimidazo[1,5-a]pyridin-yl)methyl)-1H-pyrazole-4-carboxamide, 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-ethylimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-b]pyridazin-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide, N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-546-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxamide, ethyl 2444(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate, 24(44(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic acid, 3 -(44(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3 -yl)propanoic acid, N-(1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyrimidin-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-145-(methylamino)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-3-cyclopropyl-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-5-ethynylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, methyl 2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate, methyl 3 -(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-5-yl)propanoate, N47-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methyl)-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, 2-(24(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetic acid, N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxyethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, 1-((5-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide, 1-((5-amino-8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl-d2)-14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, methyl 2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylate, N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, ethyl 3 -(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3 -yl)propanoate, N-(2-(7-chloroimidazo[1,5-a]pyridin-1-yl)ethyl)-1-((6-cyclopropylimidazo[1,2-a] pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-3 -(difluoromethyl)-1H-pyrazole-4-carboxamide, 2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylic acid, N47-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-N47-ethynylimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-3 -(difluoromethyl)-1H-pyrazole-4-carboxamide, ethyl 3 -(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acrylate, ethyl 3 -(24(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)propanoate, 3 -(24(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(morpholinomethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(oxetan-3-y1)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methoxyethoxy)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, 1-((8-acety1-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(2-hydroxypropan-2-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, ethyl 2-(24(4-(((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate, 2-(24(4-(((7-bromo-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetic acid, N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxypropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N47-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-246-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-2H-tetrazole-5-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, ethyl 2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-y1)cyclopropane-1-carboxylate, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, ethyl 1-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylate, 1-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylic acid, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-14(8-( 1 -(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, 14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-vinylimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-14(6-cyclopropy1-8-(3 -hydroxy-3 -methylbutyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, 2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)cyclopropane-1-carboxylic acid, N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-2H-1,2,3-triazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N'-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-N-cyano-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboximidamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-y1)ethyl)-1H-1,2,3-triazole-4-carboxamide, N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, 3 42H-tetrazol-5-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-y1)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, ethyl 2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylate, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide, and N4(7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1-((5,6-dimethylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-3-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, 2-(24(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylic acid, N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N47-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamide, N47-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide, N47-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-546-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide, N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-14(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxy(oxetan-3-y1)methyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-methoxyimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N47-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-148-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,4-triazole-3-carboxamide, N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-548-cyano-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide, 14(84(1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide, ethyl 2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate, 2-(24(44(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)acetic acid, N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-548-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(methylsulfonyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-546-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-1,2,4-triazole-3-carboxamide, N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-546-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4H-1,2,4-triazole-3-carboxamide, ethyl 3-(2444(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-2,2-dimethylpropanoate, ethyl 3-(2444(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate, 3-(2444(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)propanoic acid, N47-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyrimidin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, ethyl 24(44(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate, 24(44(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic acid, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(3-fluorooxetan-3-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, ethyl 3-(2444(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-2,2-dimethylpropanoate, N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(oxetan-3-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, 3-(2444(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-2,2-dimethylpropanoic acid, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, 1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropy1-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2H-tetrazol-5-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-546-cyclopropylimidazo[1,2-a]pyridin-y1)methyl)isoxazole-3-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1,2,4-oxadiazole-3-carboxamide, N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-147-cyclopropy141,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(1H-tetrazol-1-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, 1-((8-(3-amino-3-oxopropy1)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(2-cyanoethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-ylmethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, 1-((6-chloro-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6,7-dichloroimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-145-cyclopropylthieno[2,3-b]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-346-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1,2,4-oxadiazole-5-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylbenzofuran-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(difluoromethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, 14(244-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)methyl)-1H-pyrazole-4-carboxylic acid, 148-(2-(1H-tetrazol-5-yl)ethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)oxazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-chlorobenzofuran-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-y1)ethyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxotetrahydrofuran-3-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, 1-((8-((1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, 14(244-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1H-pyrazole-3-carboxylic acid, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, ethyl 3-(244-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-2,2-dimethylpropanoate, 3-(2444(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-2,2-dimethylpropanoic acid, ethyl 24244-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)acetate, 24244-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)acetic acid, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylpyrazolo[1,5-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, ethyl 5-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1,3,4-oxadiazole-2-carboxylate, 1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-145-cyclopropyl-3-(trifluoromethyl)-1H-indol-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, 24244-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3 -triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)oxy)-2-methylpropanoic acid, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(1-fluoroethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, 14(841,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(oxetan-3-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(2-oxooxazolidin-3-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-147-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-145-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylbenzofuran-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(1H-pyrazol-1-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, methyl 1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)cyclopentane-1-carboxylate, 1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)cyclopentane-1-carboxylic acid, 1-((2-((4-(((7-chloro-8-ethoxyimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)cyclopentane-1-carboxylic acid, 146-chloro-1H-indo1-2-yl)methyl)-N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, ethyl 242444(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3 -triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoate, methyl 3 -(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-2-fluoropropanoate, 3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-2-fluoropropanoic acid, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(isoxazol-4-y1)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, 1-(244-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylcarbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-1H-imidazole-4-carboxylic acid, ethyl 3-(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-y1)-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoate, 3-(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-y1)-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoic acid, 3-(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-y1)-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoic acid, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylbenzo[b]thiophen-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, 1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-1H-pyrazole-4-carboxylic acid, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-145-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-1H-indol-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-1-methyl-1H- indo1-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-chlorobenzo[b]thiophen-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-1H-benzo[d]imidazol-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(2-cyano-2-methylpropy1)-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methyl-2-(2H-tetrazol-5-y1)propyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, ethyl 3-(244-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-3-hydroxy-2,2-dimethylpropanoate, 3-(24(44(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-3-hydroxy-2,2-dimethylpropanoic acid, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-y1)methyl)-1-((6-cyclopropyl-8-(1-ethyl-5,6-dioxo-5,6-dihydro-1,2,4-triazin-4(1H)-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)difluoromethyl)-1,3,4-oxadiazole-2-carboxamide, 2-(2444(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-y1)methyl)-5-cyclopropyl-1H-indol-1-y1)acetic acid, ethyl 3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-2-methylpropanoate, 3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-2-methylpropanoic acid, methyl 2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)acetate, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(5,6-dioxo-5,6-dihydro-1,2,4-triazin-4(1H)-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, ethyl 4-(2444(7-chloro-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-4H-1,2,4-triazole-3-carboxylate, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-methyl-4H-1,2,4-triazol-4-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, ethyl 3-(24(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)propanoate, 3-(24(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)propanoic acid, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylbenzo[d]thiazol-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3,5-dimethyl-4H-1,2,4-triazol-4-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, methyl 4-(24(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)benzoate, 145-chloro-7-cyclopropy141,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylindolizin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methylthiazol-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-methyl-1H-1,2,4-triazol-1-yl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, 4-(2444(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-y1)methyl)-5-cyclopropyl-1H-indol-1-y1)benzoic acid, ethyl 4#(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-2-carboxylate, 4#(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-2-carboxylic acid, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-7-(2-oxopyrrolidin-yl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(thiazol-5-y1)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, 4-(24(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid, methyl 1424(44(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)azetidine-3-carboxylate, 1-(24(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)azetidine-3-carboxylic acid, methyl 1-(24(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)pyrrolidine-3-carboxylate, 1-(2444(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-y1)pyrrolidine-3-carboxylic acid, ethyl 24(44(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-y1)methyl)-6-cyclopropylindolizine-3-carboxylate, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-141,2,3-trimethyl-1H-indol-5-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, methyl 4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-2-carboxylate, 44(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-2-carboxylic acid, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-imidazole-4-carboxamide, methyl 24(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1H-indole-3-carboxylate, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(hydroxy(3-(hydroxymethyl)oxetan-3-y1)methyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-3-cyclopropylquinolin-6-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, 2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropy1-1H-indole-3-carboxylic acid, 64(44(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-y1)methyl)-3-cyclopropylquinoline-8-carboxamide, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrrole-3-carboxamide, N-((7-chloro-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-(1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)ethyl)-1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-y1)ethyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-(1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-l-yl)ethyl)-146-cyclopropyl-8-(hydroxy(oxetan-3-y1)methyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-84N-(2,2,2-trifluoroethyl)sulfamoyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, 1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-2H-tetrazole-5-carboxamide, N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide, 1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-imidazole-4-carboxamide, N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-2H-tetrazole-5-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-imidazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(quinoxalin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(quinoxalin-6-ylmethyl)-1H-pyrazole-4-carboxamide, 1-((8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-b]pyridazin-2-y1)methyl)-N- ((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(pyrrolidin-1-ylmethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(oxetan-3-ylmethyl)imidazo[1,2-b]pyridazin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-imidazole-4-carboxamide, 1-((8-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2-(dimethylamino)ethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(((3,3,3-trifluoro-2-hydroxypropyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2-hydroxyethoxy)methyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, 148-((2-aminoethoxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-alpyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
C. Pharmaceutical Compositions
[0093] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formulae (I)-(V) or a compound of Formulae (I)-(V) in combination with a pharmaceutically acceptable excipient (e.g., carrier).
[0094] The pharmaceutical compositions include optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein. A
compound of Formulae (I)-(III-d) included in the pharmaceutical composition may be covalently attached to a carrier moiety, as described above. Alternatively, a compound of Formulae (I)-(V) included in the pharmaceutical composition is not covalently linked to a carrier moiety.
[0095] A "pharmaceutically acceptable carrier," as used herein refers to pharmaceutical excipients, for example, pharmaceutically, physiologically, acceptable organic or inorganic carrier substances suitable for enteral or parenteral application that do not deleteriously react with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine.
Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
[0096] The compounds of the invention can be administered alone or can be coadministered to the subject. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). The preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation).
[0097] In some embodiments, a test agent as described herein can be incorporated into a pharmaceutical composition for administration by methods known to those skilled in the art and described herein for provided compounds.
D. Formulations
[0098] Compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g. intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally). Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It is also envisioned that multiple routes of administration (e.g., intramuscular, oral, transdermal) can be used to administer the compounds of the invention. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the invention.
[0099] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid.
Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substance that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
[0100] In powders, the carrier is a finely divided solid in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
[0101] The powders and tablets preferably contain from 5% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
[0102] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
[0103] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
[0104] When parenteral application is needed or desired, particularly suitable admixtures for the compounds of the invention are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. In particular, carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like. Ampoules are convenient unit dosages. The compounds of the invention can also be incorporated into liposomes or administered via transdermal pumps or patches.
Pharmaceutical admixtures suitable for use in the present invention include those described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference.
[0105] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
[0106] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
[0107] The pharmaceutical preparation is preferably in unit dosage form.
In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
[0108] The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
[0109] Some compounds may have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition. Such co-solvents include:
Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically employed at a level between about 0.01 %
and about 2% by weight.
[0110] Viscosity greater than that of simple aqueous solutions may be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing. Such agents are typically employed at a level between about 0.01% and about 2% by weight.
[0111] The compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos.
4,911,920;
5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.

E. Effective Dosages
[0112] Pharmaceutical compositions provided by the present invention include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter al/a, on the condition being treated. For example, when administered in methods to treat HAE, such compositions will contain an amount of active ingredient effective to achieve the desired result (e.g. inhibiting pKal and/or decreasing the amount of bradykinin in a subject).
[0113] The dosage and frequency (single or multiple doses) of compound administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g., the disease responsive to pKal inhibition); presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of the invention.
[0114] For any provided compound or test agent, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of decreasing pKal enzymatic activity as measured, for example, using the methods described.
[0115] Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring pKal inhibition and adjusting the dosage upwards or downwards, as described above.
[0116] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention, should be sufficient to effect a beneficial therapeutic response in the patient over time.
The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. In some embodiments, the dosage range is 0.001% to 10% (w/v). In some embodiments, the dosage range is 0.1% to 5%
(w/v).
[0117] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
F. Methods of Treatment
[0118] The present disclosure provides compounds for use in medicine. The present disclosure further provides the use of any compounds described herein for inhibiting the activity of pKal, which would be beneficial to treatment of pKal-mediated diseases and conditions.
Exemplary pKal-mediated disorders include edema, which refers to swelling in the whole body of a subject or a part thereof due to inflammation or injury when small blood vessels become leaky and releases fluid into nearby tissues. In some examples, the edema is HAE. In other examples, the edema occurs in eyes, e.g., diabetic macular edema (DME). The present disclosure provides methods of inhibiting the activity of pKal. In certain embodiments, the application provides a method of inhibiting the activity of pKal in vitro via contacting any of the compounds described herein with pKal molecules in a sample, such as a biological sample.
In certain embodiments, the application provides a method of inhibiting the activity of pKal in vivo via delivering an effective amount of any of the compounds described herein to a subject in need of the treatment through a suitable route.
[0119] In certain embodiments, the methods comprise administering to a subject in need thereof (e.g., a subject such as a human patient with edema) any of the compounds described herein or a pharmaceutically acceptable salt thereof In certain embodiments, the methods comprise administering a compound of Formulae (I)-(V), or a pharmaceutically acceptable salt or composition thereof, to a subject in need thereof. In some embodiments, the method comprises administering a pharmaceutical composition comprising a compound of Formulae (I)-(V), or a pharmaceutically acceptable salt to a subject in need thereof.
[0120] In certain embodiments, the subject to be treated by any of the methods described herein is a human patient having, suspected of having, or at risk for edema, for example, HAE or diabetic macular edema (DME). A subject having an edema can be identified by routine medical examination, e.g., laboratory tests. A subject suspected of having an edema might show one or more symptoms of the disease/disorder. A subject at risk for edema can be a subject having one or more of the risk factors associated with the disease, for example, deficiency in C1-INH as for HAE.
[0121] In certain embodiments, provided herein are methods of alleviating one or more symptoms of HAE in a human patient who is suffering from an HAE attack. Such a patient can be identified by routine medical procedures. An effective amount of one or more of the provided compounds can be given to the human patient via a suitable route, for example, those described herein. The compounds described herein may be used alone, or may be used in combination with other anti-HAE agents, for example, a Cl esterase inhibitor (e.g., Cinryze or Berinert ), a pKal inhibitor (e.g., ecallantide or lanadelumab) or a bradykinin B2 receptor antagonist (e.g., Firazyr ).
[0122] In other embodiments, provided herein are methods or reducing the risk of HAE
attack in a human HAE patient who is in quiescent stage. Such a patient can be identified based on various factors, including history of HAE attack. An effective amount of one or more of the compounds can be given to the human patient via a suitable route, for example, those described herein. The compounds described herein may be used alone, or may be used in combination with other anti-HAE agents, for example, a Cl esterase inhibitor (e.g., Cinryze or Berinert ), a pKal inhibitor (e.g., ecallantide or lanadelumab) or a bradykinin B2 receptor antagonist (e.g., Firazyr ).
[0123] In yet other embodiments, provided herein are prophylactic treatment of HAE in human patients having risk to HAE attacks with one or more of the compounds described herein.
Patients suitable for such prophylactic treatment may be human subjects having history of HAE
attacks (e.g., human subjects experiencing more than 2 attacks per month).
Alternatively, patients suitable for the prophylactic treatment may be human subjects having no HAE attack history but bearing one or more risk factors for HAE (e.g., family history, genetic defects in Cl-INH gene, etc.) Such prophylactic treatment may involve the compounds described herein as the sole active agent, or involve additional anti-HAE agents, such as those described herein.
[0124] In certain embodiments, provided herein are methods for preventing or reducing edema in an eye of a subject (e.g., a human patient). In some examples, the human patient is a diabetic having, suspected of having, or at risk for diabetic macular edema (DME). DME is the proliferative form of diabetic retinopathy characterized by swelling of the retinal layers, neovascularization, vascular leak, and retinal thickening in diabetes mellitus due to leaking of fluid from blood vessels within the macula. To practice this method, an effective amount of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, may be delivered into the eye of the subject where treatment is needed. For example, the compound may be delivered by intraocular injection, or intravitreal injection. A subject may be treated with the compound as described herein, either as the sole active agent, or in combination with another treatment for DME. Non-limiting examples of treatment for DME include laser photocoagulation, steroids, VEGF pathway targeting agents (e.g., Lucentis (ranibizumab) or Eylea (aflibercept)), and/or anti-PDGF agents.
[0125] In certain embodiments, the methods disclosed herein comprise administering to the subject an effective amount of a compound of Formulae (I)-(V), or a pharmaceutically acceptable salt or composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.
[0126] In certain embodiments, the subject being treated is an animal.
The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject being treated is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat.
In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal.
[0127] Certain methods described herein may comprise administering one or more additional pharmaceutical agent(s) in combination with the compounds described herein. The additional pharmaceutical agent(s) may be administered at the same time as the compound of Formulae (I)-(V), or at different times than the compound of Formulae (I)-(V).
For example, the compound of Formulae (I)-(V) and any additional pharmaceutical agent(s) may be on the same dosing schedule or different dosing schedules. All or some doses of the compound of Formulae (I)-(V) may be administered before all or some doses of an additional pharmaceutical agent, after all or some does an additional pharmaceutical agent, within a dosing schedule of an additional pharmaceutical agent, or a combination thereof The timing of administration of the compound of Formulae (I)-(V) and additional pharmaceutical agents may be different for different additional pharmaceutical agents.
[0128] In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of an edema, such as HAE or DME. Examples of such agents are provided herein.
[0129] The following numbered embodiments, while non-limiting, are exemplary of certain aspects of the present disclosure:
1. A compound of Formula (I):

N¨\c/
R7 \
N N (I) R6 R47 CyA CyB

or a pharmaceutically acceptable salt thereof, wherein:
CyA is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyenel having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyA
is substituted with 0-4 RA groups;
each RA is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
CyB is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-RB groups;
each RB is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
L is selected from -QC(R)2-, -C(R)2Q-, -QC(Q)-, -C(Q)Q-, -C(R)2QC(0)-, and -C(0)QC(R)2-, wherein each Q is independently a monovalent or divalent group as valency allows, selected from the group consisting of 0, N(R), or (S);
RI-, R2, R3, and R4 are independently selected from hydrogen and C1-6 aliphatic;

R5, R6, R7, R8, and R9 are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur;
with the proviso that the compound is other than N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-243-chloroquinolin-6-yl)methyl)isonicotinamide.
2. The compound of embodiment 1, wherein the compound is of Formula (IV):

R"
L-CyA
w4 R13 or a pharmaceutically acceptable salt thereof, wherein:
CyA is a 5-membered heteroarylene having 1-4 heteroatoms selected from oxygen or nitrogen, wherein CyA is substituted with 0-3 RA groups;
L is selected from -NC(0)- and -C(0)N-;
R6, R8, and R9 are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
R7 is -F, -Cl, or -Br;
W4 is carbon or nitrogen;
Rm and R" are each optionally present, and if present are independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
R1-3 is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C2-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
K is optionally present, and if present and is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C3-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.

3. The compound of any one of the preceding embodiments, wherein the compound is of Formula (V):

N

R"
L -CyA

RI

or a pharmaceutically acceptable salt thereof, wherein:
CyA is a 5-membered heteroarylene having 1-4 nitrogens, wherein when CyA
comprises 3 Vi(-N I
nitrogens, CyA is not * H =
L is selected from -NC(0)- and -C(0)N-;
R6, R8, and R9 are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
R7 is -F, -Cl, or -Br;
R' is optionally present, and if present is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
K is optionally present, and if present is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from Ci.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
R13 is selected from -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -OC(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- or 5-7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
K is optionally present, and if present and is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C3-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
4. The compound of any one of the preceding embodiments, wherein L is selected from -QC(R)2-, -C(R)2Q-, -C(Q)Q-, or -C(R)2QC(0)-, wherein Q is independently a monovalent or divalent group as valency allows, selected from 0 or N(R).
5. The compound of any one of of the preceding embodiments, wherein L is -N(H)C(0)-.
6. The compound of any one of of the preceding embodiments, L is -C(0)N(H)-.
The compound of any one of the preceding embodiments, wherein L is selected from the group consisting of:
N Nc -1/2.( 5\14 \#

RNe.

wherein # represents to point of attachment to CyA.
7. The compound of any one of the preceding embodiments, wherein L is selected from the group consisting of:
Nje Ye.14 wherein # represents to point of attachment to CyA.
8. The compound of any one of the preceding embodiments, wherein L is:

0 , wherein # represents to point of attachment to CyA.
9. The compound of any one of the preceding embodiments, wherien le and R4 are hydrogen.
10. The compound of any one of the preceding embodiments, wherein the compound is of Formula (II):
CyB
i\ (II) or a pharmaceutically acceptable salt thereof, wherein:
CyA is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyenel having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyA
is substituted with 0-4 RA groups;
each RA is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from Ci.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;

CyB is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-RB groups;
each RB is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
RI- and R2 are independently selected from hydrogen and C1-6 aliphatic;
R6 and R7 are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;

or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur;
with the proviso that the compound is other than N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-243-chloroquinolin-6-yl)methyl)isonicotinamide.
11. The compound of any one of the preceding embodiments, with the proviso that CyA is a group other than pyridinediyl and the compound is other than N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-243-chloroquinolin-6-yl)methyl)isonicotinamide.
12. The compound of any one of the preceding embodiments, wherein CyA is selected from 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur wherein CyA is substituted with 0-4 RA groups.
13. The compound of any one of the preceding embodiments, wherein CyA is a 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyA is substituted with 0-3 RA groups.
14. The compound of any one of the preceding embodiments, wherein CyA is a 6-membered heteroarylene having 1 nitrogen, wherein CyA is substituted with 0-3 RA
groups.
15. The compound of any one of the preceding embodiments, wherein CyA is selected from either:
(R )03 (RA)0-3 or wherein * represents to point of attachment to L.
16. The compound of any one of the preceding embodiments, wherein CyA is a 7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur wherein CyA is substituted with 0-4 RA groups.

17. The compound of any one of the preceding embodiments, wherein CyA is a 9-membered bicyclic heteroarylene having 2 nitrogens wherein CyA is substituted with 0-4 RA groups.
18. The compound of any one of the preceding embodiments, wherein CyA is a pyrrolopyridinediyl substituted with 0-4 RA groups.
19. The compound of any one of the preceding embodiments, wherein CyA is a 5-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyA is substituted with 0-2 RA groups.
20. The compound of any one of the preceding embodiments, wherein CyA is selected from the group consisting of: pyrrolediyl substituted with 0-3 RA groups, pyrazolediyl substituted with 0-2 RA groups, triazolediyl substituted with 0-1 RA groups, thiazolediyl substituted with 0-1 RA groups, imidazolediyl substituted with 0-2 RA groups, oxazolediyl substituted with 0-1 RA
groups, isoxazolediyl substituted with 0-1 RA groups, unsubsituted tetrazolediyl, unsubstituted oxadiazolediyl, and unsubstituted thiadiazolediyl.
21. The compound of any one of the preceding embodiments, wherein CyA is selected from the group consisting of:
\ N
* (RA)0-3 A
N Roi (R yzz. :1\1-1 N
(RA)0_2 N¨N N¨N
-1 ksH
õ
N-NH
),0---1 (RA 0_1- H
--(RA)0_2 (RA. (R

___N N7r-N
vc,\sN j\:RAN1-10-i (R yzz, (RA)0-2 ¨() N_I* (RA ox1\14 (RA 0_1k1=\,NA* (RAE

(..._r;--; OH*
(RA)0-2 -1\1 WC) NH) (RA 0-1JIL * H*
wherein * represents to point of attachment to L.
22. The compound of any one of the preceding embodiments, wherein CyA is a 5-membered heteroarylene having 1-4 heteroatoms selected from oxygen or nitrogen.
23. The compound of any one of the preceding embodiments, wherein CyA is a 5-membered heteroarylene having 1-4 nitrogens.
24. The compound of any one of the preceding embodiments, wherein CyA is a 5-membered heteroarylene having 1-4 nitrogen, wherein when CyA comprises 3 nitrogen, it is not a a 1,2,4, triazolediyl.
25. The compound of any one of the preceding embodiments, wherein CyA is selected from the group consisting of:
NzsN __.N
*\(C, wherein * represents to point of attachment to L.
26. The compound of any one of the preceding embodiments, wherein the compound is of Formula (III-a) through (III-d):

N

----- NH

N,N
A N c_13 (RA)0-1 )(CyB
(R )0-1 V-Y

(III-a) (HI-b) N

z/N,N N, CyB Nm,\ _cys R2 RI , (III-c) (III-d) or a pharmaceutically acceptable salt thereof, wherein:
each RA is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from Ci.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
CyB is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-RB groups;

each RB is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
RI- and R2 are independently selected from hydrogen and C1-6 aliphatic;
R6 and R7 are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
27. The compound of any one of the preceding embodiments, wherein CyB is selected from phenyl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-5 RB groups.
28. The compound of any one of the preceding embodiments, wherein CyB is a 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-5 RB groups.
29. The compound of any one of the preceding embodiments, wherein CyB is a 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-5 RB groups.
30. The compound of any one of the preceding embodiments, wherein CyB is a 10-membered bicyclic heteroaryl having 1 nitrogen, wherein CyB is substituted with 0-5 RB
groups.
31. The compound of any one of the preceding embodiments, wherein CyB is selected from the group consisting of: quinolonyl group substituted with 0-5 RB groups and quinoxalinyl group substituted with 0-5 RB groups.
32. The compound of any one of the preceding embodiments, wherein CyB is selected from the group consisting of:
N
(RB)0_5 NI7=:1(RB)0-5 =
33. The compound of any one of the preceding embodiments, wherein CyB is a 9-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-5 RB groups.
34. The compound of any one of the preceding embodiments, wherein CyB is RI2 w3 RI3 w4 RIO

wherein:

Iv% w2, W and W4 are independently selected from carbon and nitrogen;
R10, R11, R12, K-13, and R14 are each optionally present when attached to a carbon atom, and if present correspond to an occurrence of RB independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
35. The compound of any one of the preceding embodiments, W4 is carbon.
36. The compound of any one of the preceding embodiments, W4 is nitrogen.
37. The compound of any one of the preceding embodiments, Wl is nitrogen and W2, W3 and W4 are carbon.
38. The compound of any one of the preceding embodiments, W2 is nitrogen and Wl, W3 and W4 are carbon.
39. The compound of any one of the preceding embodiments, nitrogen and Wl and W4 are carbon.
40. The compound of any one of the preceding embodiments, W2 and W4 are nitrogen and Wl and W3 are carbon.

41. The compound of any one of the preceding embodiments, wherein CyB is selected from the group consisting of imidazopyridinyl substituted with 0-5 RB groups, pyrazolopyridinyl substituted with 0-5 RB groups, pyrrolopyridinyl substituted with 0-4 RB
groups, triazolopyridinyl substituted with 0-4 RB groups, imidazopyrimidinyl substituted with 0-4 RB
groups, imidazopyridazinyl substituted with 0-4 RB groups, indolizinyl substituted with 0-5 RB
groups, and pyrazolopyrimidinyl substituted with 0-4 RB groups.
42. The compound of any one of the preceding embodiments, wherein CyB is selected from the group consisting of:
HN N I
N N rriN

N Ni jN N
(RB)o-5 (RB)o-5 (RB)o-4 (RB)o-4 (RB)o-4 (RB)o-4 N N
(RB)o-5 (RB)o-4 43. The compound of any one of the preceding embodiments, wherein CyB is RI2 w3 I
I

R

wherein:
W2 is selected from carbon, nitrogen, oxygen, and sulfur;
W3, and W4 are independently selected from carbon and nitrogen;
R10, R11, R12, K-13, and R14 are each optionally present when attached to a carbon atom, and if present correspond to an occurrence of RB independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
44. The compound of any one of the preceding embodiments, wherein CyB is selected from the group consisting of a indolyl substituted with 0-5 RB groups, a benzofuranyl substituted with 0-5 RB groups, a benzimidazolyl substituted with 0-4 RB groups, and a thienopyridinyl substituted with 0-4 RB groups.
45. The compound of any one of the preceding embodiments, wherein CyB is selected from the group consisting of:

N)( (RB)O-5 (RB)O-5 (RB)O-4 (RB)O-4 (RB)o-4 46. The compound of any one of the preceding embodiments, wherein each RA
is independently selected from an optionally substituted group selected from C1.6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
47. The compound of any one of the preceding embodiments, wherein substituents on an optionally substituted RA group are independently halogen, (CH2)0.4R , -(CH2)0.40R ; and -(CH2)0.4C(0)0R , wherein each R is independently hydrogen, Ci.6 aliphatic, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
48. The compound of any one of the preceding embodiments, wherein a single instance of RA
is C1.6 aliphatic substituted with halogen.
49. The compound of any one of the preceding embodiments, wherein a single instance of RA
is C1-6 aliphatic substituted with -(CH2)0_40R , wherein R is hydrogen or C1-6 aliphatic.
50. The compound of any one of the preceding embodiments, wherein a single instance of RA
is C1-6 aliphatic substituted with -(CH2)0.4C(0)0R , wherein R is hydrogen or Ci.6 aliphatic.
51. The compound of any one of the preceding embodiments, wherein a single instance of RA
is C1-6 aliphatic is substituted with 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
52. The compound of any one of the preceding embodiments, wherein a single instance of RA
is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, a single instance of RA is optionally substituted cyclopropyl.
In some embodiments, a single instance of RA is cyclopropyl substituted with -(CH2)0.4C(0)0R
and R is hydrogen or C1-6 aliphatic.
53. The compound of any one of the preceding embodiments, wherein R5, R6, R7, R8, and R9 are independently selected from hydrogen, halogen, -CN, -N(R)2, -OR, or an optionally substituted group selected from C1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, wherein each R is independently hydrogen or C1-6 aliphatic.
54. The compound of any one of the preceding embodiments, wherein R5, le, and R9 are hydrogen.

55. The compound of any one of the preceding embodiments, wherein R6 is selected from hydrogen or halogen.
56. The compound of any one of the preceding embodiments, wherein R6 is hydrogen.
57. The compound of any one of the preceding embodiments, wherein R6 is halogen.
58. The compound of any one of the preceding embodiments, wherein R6 is -F.
59. The compound of any one of the preceding embodiments, wherein R6 is -Cl.
60. The compound of any one of the preceding embodiments, wherein R6 is -Br.
61. The compound of any one of the preceding embodiments, wherein R7 is selected from halogen or an optionally substituted C1.6 aliphatic.
62. The compound of any one of the preceding embodiments, wherein R7 is halogen.
63. The compound of any one of the preceding embodiments, wherein R7 is -F.
64. The compound of any one of the preceding embodiments, wherein R7 is -Cl.
65. The compound of any one of the preceding embodiments, wherein R7 is -Br.
66. The compound of any one of the preceding embodiments, wherein R7 is optionally substituted C1.6 aliphatic.
67. The compound of any one of the preceding embodiments, wherein R" is optionally present, and if present is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
68. The compound of any one of the preceding embodiments, wherein R" is selected from -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
69. The compound of any one of the preceding embodiments, wherein le3 is selected from halogen, optionally substituted C 1.6 aliphatic, and optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl.
70. The compound of any one of the preceding embodiments, wherein le3 is halogen.
71. The compound of any one of the preceding embodiments, wherein le3 is optionally substituted C1-6 aliphatic.
72. The compound of any one of the preceding embodiments, wherein le3 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl.
73. The compound of any one of the preceding embodiments, wherein le3 is an optionally substituted 3- or 5-7-membered saturated or partially unsaturated monocyclic carbocyclyl.
74. The compound of any one of the preceding embodiments, wherein le3 is an optionally substituted cyclopropyl.
75. The compound of any one of the preceding embodiments, wherein the compound is any one of compounds I-1 through 1-303, or a pharmaceutically acceptable salt thereof.
76. A pharmaceutical composition comprising any one of the preceding compounds.
77. The pharmaceutical composition comprising any one of the preceding compounds further comprising a pharmaceutically acceptable excipient.
78. The pharmaceutical composition of any one of embodiments 76-77, wherein the composition is suitable for oral administration.
79. The pharmaceutical composition of any one of embodiments 76-77, wherein the composition is suitable for admistration by injection.
80. A method of treating a plasma kallikrein-mediated disease or disorder using a compound or composition of any one of the preceding embodiments.

81. The method of embodiment 80, wherein the disease or disorder is hereditary angioedema or diabetic macular edema.
82. A method of treating hereditary angioedema or diabetic macular edema comprising administering to a patient in need thereof a compound of any one of the preceding embodiments.
[0130] The following numbered embodiments, while non-limiting, are also exemplary of certain aspects of the present disclosure:
83. A compound of Formula (I):

N7( R7 \
N N (I) R6 R4 CyA CyB

or a pharmaceutically acceptable salt thereof, wherein:
CyA is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyenel having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyA
is substituted with 0-4 RA groups;
each RA is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
CyB is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-RB groups;
each RB is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
L is selected from -QC(R)2-, -C(R)2Q-, -QC(Q)-, -C(Q)Q-, -C(R)2QC(0)-, and -C(0)QC(R)2-, wherein each Q is independently a monovalent or divalent group as valency allows, selected from the group consisting of 0, N(R), or (S);
RI-, R2, R3, and R4 are independently selected from hydrogen and C1-6 aliphatic;
R5, R6, R7, R8, and R9 are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur;
with the proviso that the compound is other than N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-243-chloroquinolin-6-yl)methyl)isonicotinamide.
84. The compound of embodiment 83, wherein the compound is of Formula (II):
CyA CyB
(II) 0 R2 Ri or a pharmaceutically acceptable salt thereof.
85. The compound of any one of the preceding embodiments, with the proviso that CyA is a group other than pyridinediyl and the compound is other than N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-243-chloroquinolin-6-yl)methyl)isonicotinamide.
86. The compound of any one of the preceding embodiments, wherein CyA is selected from 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur wherein CyA is substituted with 0-4 RA groups.
87. The compound of any one of the preceding embodiments, wherein CyA is selected from the group consisting of pyrrolopyridinediyl substituted with 0-4 RA, pyrazolediyl substituted with 0-2 RA groups, triazolediyl substituted with 0-1 RA groups, thiazolediyl substituted with 0-1 RA
groups, imidazolediyl substituted with 0-2 RA groups, oxazolediyl substituted with 0-1 RA
groups, isoxazolediyl substituted with 0-1 RA groups, unsubsituted tetrazolediyl, unsubstituted oxadiazolediyl, and unsubstituted thiadiazolediyl.
88. The compound of any one of the preceding embodiments, wherein CyA is selected from the group consisting of:
NI \
((lR Ws--N
sN-1 (RA)o-i VA)0_2 ':µ(((RA)o-i *\.(--1\1 N¨N N¨N
VCSH ,S(SH
N N¨NH

(RA.),,o_et H (RAt (R ) 0 N¨ N¨
\
(RA (RA ANH
õ N
wherein * represents to point of attachment to L.
89. The compound of any one of the preceding embodiments, wherein the compound has a structure selected from the group consisting of:
NN
N

NH

N, 'N
I
(RA)0-1 )(CYB
(100-1 )cCyB

(III-a) (III-b) N-N

z/N,N N, 'N
OcyB N-N\ _cys R2 RI R,, (III-c) (III-d) or a pharmaceutically acceptable salt thereof.
90. The compound of any one of the preceding embodiments, wherein CyB is a 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-5 RB groups.
91. The compound of any one of the preceding embodiments, wherein CyB is R12 w3 I
N

R) wherein:
w2, W3, and W4 are independently selected from carbon and nitrogen;
R10, R11, R12, K-13, and R14 are each optionally present when attached to a carbon atom, and if present correspond to an occurrence of RB independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
92. The compound of any one of the preceding embodiments, wherein CyB is selected from the group consisting of imidazopyridinyl substituted with 0-5 RB groups, pyrazolopyridinyl substituted with 0-5 RB groups, pyrrolopyridinyl substituted with 0-4 RB
groups, triazolopyridinyl substituted with 0-4 RB groups, imidazopyrimidinyl substituted with 0-4 RB
groups, imidazopyridazinyl substituted with 0-4 RB groups, indolizinyl substituted with 0-5 RB
groups, and pyrazolopyrimidinyl substituted with 0-4 RB groups.
93. The compound of any one of the preceding embodiments, wherein CyB is selected from the group consisting of:
¨N
HN N
N
h IN
h II
Nr,) (RB).5 (RB).5 (RB)0-4 (RB)0-4 (RB)0-4 (RB)0-4 N N
(RB)o-5 94. The compound of any one of embodiments 83-90, wherein CyB is RI2 w3 R

wherein:
W2 is selected from carbon, nitrogen, oxygen, and sulfur;
W3, and W4 are independently selected from carbon and nitrogen;
R10, R11, R12, K-13, and R14 are each optionally present when attached to a carbon atom, and if present correspond to an occurrence of RB independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
95. The compound of any one of embodiments 83-90 and 94, wherein CyB is selected from the group consisting of a indolyl substituted with 0-5 RB groups, a benzofuranyl substituted with 0-5 RB groups, a pyrazolopyrimidinyl substituted with 0-4 RB groups, a benzimidazolyl substituted with 0-4 RB groups, and a thienopyridinyl substituted with 0-4 RB
groups.
96. The compound of any one of embodiments 83-90 and 94-95, wherein CyB is selected from the group consisting of:

N)( (RB )0-5 (RB )0-5 (RB)0-4 (RB)0-4 (RB )0-4 97. The compound of any one of embodiments 83-90, wherein CyB is a quinolondiyl group substituted with 0-5 RB groups.
98. The compound of embodiment any one of embodiments 83-90 and 97, wherein CyB is N B
- (R)0-5 99. The compound of any one of the preceding embodiments, wherein L is -N(H)C(0)- or embodiments, L is -C(0)N(H)-.
100. The compound of any one of the preceding embodiments, wherein R6 is halogen.
101. The compound of embodiment 91 or 94, wherein R13 is selected from halogen, optionally substituted C 1.6 aliphatic, and optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl.
102. The compound of embodiment 91 or 94, wherein R13 is an optionally substituted cyclopropyl.
103. A pharmaceutical composition comprising any one of the preceding compounds.
104. The pharmaceutical composition of embodiment 103 further comprising a pharmaceutically acceptable excipient.

105. The pharmaceutical composition of any one of embodiments 103-104, wherein the composition is suitable for oral administration.
106. The pharmaceutical composition of any one of embodiments 103-104, wherein the composition is suitable for admistration by injection.
107. A method of treating a plasma kallikrein-mediated disease or disorder using a compound any one of embodiments 83-102 or composition according to of any one of embodiments 103-106.
108. The method of embodiment 27, wherein the disease or disorder is hereditary angioedema or diabetic macular edema.
109. A method of treating hereditary angioedema or diabetic macular edema comprising administering to a patient in need thereof a compound of any one of embodiments 83-102 or composition according to of any one of embodiments 103-106.
IV. EXAMPLES
Example 1 Scheme 1 0\\ fr---1\11 CI LiOH
NI-- OH
Cs2CO3, MeCN, 80 C THF/H20, 100C

N N CI
Ny4 N¨ HN CI
HATU, DIPEA, DMF 1-1 N N
[0131] Synthesis of methyl 1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxylate. A mixture of 3-chloro-6-(chloromethyl)quinoline (200 mg, 0.95 mmol), methyl 1H-pyrazole-4-carboxylate (1.2 g, 0.95 mmol) and Cs2CO3 (930 mg, 2.85 mmol) in MeCN (5 mL) was stirred at 70 C for 1 h. Water was added and extracted with Et0Ac, the combined organic layers were concentrated and purified by silcial gel column (EA/PE =
1/10) to give methyl 1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxylate (200 mg, yield: 78%) as a white solid. ESI-MS [M+H]+: 302.1.
[0132] Synthesis of 1-((3-chloroquinolin-6-yHmethyl)-1H-pyrazole-4-carboxylic acid.
A mixture of methyl 1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxylate (200 mg, 0.66 mmol) and LiOH (158 mg, 6.6 mmol) in THF (10 mL) and H20 (5 mL) was stirred at 100 C for overnghit. Water was added and the pH value of the mixture was adjusted to 4-5 by added 1 M HC1 solution. The mixture was then extracted with Et0Ac (20 mL x 3), the combined organic layers were concentrated to give 1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxylic acid (150 mg, yield: 72%) as a white solid, which was used into next step without further purification. ESI-MS [M+H]: 288Ø
[0133] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((3-chloroquinolin-6-yHmethyl)-1H-pyrazole-4-carboxamide (I-1). A mixture of 1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxylic acid (50 mg, 0.17 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (37 mg, 0.17 mmol), and HATU (98 mg, 0.06 mmol) and DIPEA (66 mg, 0.51 mmol) in DNIF (2 mL) was stirred at RT overnight.
Water (10 mL) was added and extracted with Et0Ac (20 mL x 3), the combined organic layers were concentrated and purified by prep-HPLC to give N47-chloroimidazo[1,5-a]pyridin-yl)methyl)-143-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (17.3 mg, yield: 20%) as a white solid. ESI-MS [M+H]: 451.1. Purity: 99.49%. IIINNIR (400 MHz, DMS0): 6 8.88 (d, J = 2.2 Hz, 1H), 8.64-8.58 (m, 2H), 8.36-8.31 (m, 3H), 8.03 (d, J = 8.7 Hz, 1H), 7.94 (s, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.7 Hz, 1H), 6.67 (dd, J = 7.4, 1.8 Hz, 1H), 5.56 (s, 2H), 4.57 (d, J = 5.4 Hz, 2H).
Example 2 Scheme 2 õ,...,Cr) /CI NN

CI
CI OH NH NN
CI
HATU DIPEA Cs,CO3, DMF, rt DMF, rt, overnight
[0134] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide. To a mixture of (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (2.5 g, 11.52 mmol), 1H-pyrazole-4-carboxylic acid (920 mg, 8.23 mmol), HATU
(3.9 g, 10.29 mmol) in DMF (300 mL) was added DIPEA (7.3 mL, 41.14 mmol). The resulting reaction mixture was stirred at RT for 14 h. The reaction was then concentrated to remove most of the DMF, and the residue was poured into H20 (150 mL) and brown solid was precipitated out. The precipitate was filtered and the filtrated cake was triturated with DCM and dried to give the N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide, which was used into next step without further purification (2 g, yield: 88%). ESI-MS [M+H]+:
276.2.
[0135] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-2).
A mixture of N((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (2 g, 7.27 mmol), 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1.96 g, 9.45 mmol) and Cs2CO3 (7.1 g, 21.81 mmol) in DNIF (50 mL) was stirred at 50 C for 14 h. H20 (200 mL) was added, extracted with Et0Ac (300 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/Me0H = 10/1) to give the N-((7-chloroimidazo[1,5-a]pyridin-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide as a white solid (1.5 g, yield: 46%). LCMS m/z: 446.1 [M+H]+, tR = 1.040 min, purity: 98.6% (214 nm), 97.4% (254 nm). 1HNMR (400 MHz, DMS0): 6 8.58 (t, J = 5.7 Hz, 1H), 8.32-8.29 (m, 3H), 8.20 (s, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.00-6.98 (m, 1H), 6.64 (dd, J = 7.5, 2.0 Hz, 1H), 5.38 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 1.91 (ddd, J = 13.5, 8.4, 5.1 Hz, 1H), 0.99-0.87 (m, 2H), 0.77-0.61 (m, 2H).
Example 3 Scheme 3 ci 0 0 ci CI I N
H
OH ________________________________________ "N N
I N HATU, DIPEA, DMF

CI
[0136] Synthesis of N4(7-chloroimidazo[1,5-alpyridin-1-y1)methyl)-2-((3-chloroquinolin-6-y1)methyl)isonicotinamide (1-3). To a solution of 2-((3-chloroquinolin-6-yl)methyl)isonicotinic acid (60 mg, 0.20 mmol), (7-chloroimidazo[1,5-a]pyridin-yl)methanamine (44 mg, 0.24 mmol) and HATU (115 mg, 0.30 mmol) in DIVIF (8 mL) was added DIPEA (77 mg, 0.60 mmol). The resulting reaction was stirred at RT for 12 h. H20 (20 mL) was added, extracted with Et0Ac (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with prep-TLC (DCM/Me0H = 10/1) to give the N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-y1)methyl)isonicotinamide (20 mg, yield: 22%) as a white solid. ESI-MS
[M+H]+: 462Ø Purity: 98.3%. 111NMR (400 MHz, DMS0): 6 9.27-9.24 (m, 1H), 8.84-8.81 (m, 1H), 8.62 (d, J = 5.0 Hz, 1H), 8.51 (s, 1H), 8.38-8.26 (m, 2H), 7.97 (d, J =
8.6 Hz, 1H), 7.90-7.69 (m, 4H), 7.62 (d, J = 4.7 Hz, 1H), 6.66 (d, J = 7.4 Hz, 1H), 4.64 (d, J = 5.5 Hz, 2H), 4.35 (s, 2H).
Example 4 Scheme 4 NH2 Boc,O, NHBoc 13 13 NHBoc NH2 CI DIPEA CI HC!, Me0H
DCM, rt, 12 h N Pd(PPh3)4, K2CO3 dioxane/H2O, 100 C, 12 h ,vCr---121)_\
=====.. N N
10.1,0H HN
HATU, DIPEA, DMF V-0¨\\ 1-4
[0137] Synthesis of tert-butyl ((7-chloroimidazo11,5-alpyridin-1-yl)methyl)carbamate. A mixture of (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (300 mg, 1.65 mmol), Boc20 (537 mg, 2.4 mmol) and DIPEA (1.06 g, 8.25 mmol) in DCM (40 mL) was stirred at RT for 12 h. The reaction was quenched with H20 (50 mL), extracted with DCM (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel chromatography (PE/EA = 1/1) to give the tert-butyl ((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (210 mg, yield: 45%) as a yellow solid. ESI-MS [M+H]+: 282.2.
[0138] Synthesis of tert-butyl ((7-methylimidazo[1,5-a] pyridin-1-yl)methyl)carbamate. A mixture of tert-butyl ((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (210 mg, 0.75 mmol), 2,4,6-trimethy1-1,3,5,2,4,6-trioxatriborinane (188 mg, 1.5 mmol), Pd(PPh3)4 (87 mg, 0.075 mmol) and K2CO3(310 mg, 2.25 mmol) in dioxane/H20 (10 mL/1 mL) in a sealed tube was stirred at 100 C for 12 h. H20 (30 mL) was added to the reaction, extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel chromatography (EA/PE = 1/1) to give the tert-butyl ((7-methylimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (150 mg, yield: 77%) as a light yellow solid. ESI-MS [M+H]+: 262.3.
[0139] Synthesis of (7-methylimidazo11,5-a] pyridin-1-yl)methanamine hydrochloride. To a solution of tert-butyl ((7-methylimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (150 mg, 0.57 mmol) in Me0H (3 mL) was added HC1 (4 M
solution in Me0H, 3 mL). The resulting reaction was stirred at RT for 2 h. The reaction was concentrated in vacuo to give the (7-methylimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (95 mg, yield: 85%). ESI-MS [M+H]+: 162.2.
[0140] Synthesis of 14(6-cyclopropylimidazo11,2-alpyridin-2-yl)methyl)-N-((7-methylimidazo11,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1-4). To a solution of 1((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (136 mg, 0.48 mmol), (7-methylimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (95 mg, 0.48 mmol) and HATU (238 mg, 0.63 mmol) in DMF (15 mL) was added DIPEA (310 mg, 2.4 mmol). The resulting reaction was stirred at RT for 12 h. H20 (25 mL) was added to the reaction, extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with prep-TLC
(DCM/Me0H = 10/1) to give the 14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-methylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (21 mg, yield: 10%) as a white solid. ESI-MS [M+H]+: 426.2. Purity: 96.4%. IENNIR (400 MHz, DMS0): 6 8.47 (s, 1H), 8.39-8.04 (m, 5H), 7.86 (s, 1H), 7.71 (s, 1H), 7.40-7.35 (m, 2H), 6.99 (d, J =
9.1 Hz, 1H), 6.45 (d, J = 7.0 Hz, 1H), 5.38 (s, 2H), 4.54 (d, J = 4.5 Hz, 2H), 2.20 (s, 3H), 1.95-1.88 (m, 1H), 0.93-0.90 (m, 2H), 0.68-0.63 (m, 2H).
Example 5 Scheme 5 Brrr/HCI

\N N
HO)Lfj\I
N\ eN HATU, DIPEA, DMF

Br
[0141] Synthesis of N-((7-bromoimidazo[1,5-a1pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide. (1-5) To a solution of 1((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (154 mg, 0.54 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine (120 mg, 0.54 mmol) and HATU (310 mg, 0.82 mmol) in DMF (4 mL) was added DIPEA (210 mg, 1.63 mmol). The resulting reaction was stirred at RT for 12 h. H20 (20 mL) was added, extracted with Et0Ac (25 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentered in vacuo to give the crude, which was purified with prep-TLC (DCM/Me0H = 10/1) to give the N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (24 mg, yield: 9%) as a white solid. ESI-MS [M+H]+:
490.1. Purity: 98.24%. 111 NMR (400 MHz, DMS0): 6 8.57 (t, J = 8.0 Hz, 1H), 8.32 (d, J = 4.2 Hz, 2H), 8.24 (d, J = 7.5 Hz, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.71 (s, 1H), 7.39 (d, J
= 9.4 Hz, 1H), 6.99 (d, J = 9.3 Hz, 1H), 6.72 (dd, J = 7.4, 1.8 Hz, 1H), 5.38 (s, 2H), 4.54 (d, J =
5.7 Hz, 2H),1.98-1.87 (m, 1H), 1.01-0.76 (m, 2H), 0.76-0.55 (m, 2H).

Example 6 Scheme 6 NH, µµ
0 g-CI -- I ; - 0 0 ,0H

õ.4, 0\ 0 N )L
0 0 j<
TFA, 0 C, 2 h S , NFI2 S 1 -0y0 ______ '- 01 µS\
H ,0 õ N NH

TEA, t-BuoMe, DCM, 0 C to rt, 1 h 0 HO
N-N
CI
0 r OH CI NH

NaBH OH
Pyridine, Me0H, N
N , 1\1 SOCl2, DCM, NH
______________________________________________________________________ ..-i Pyridine, 100 C, N , 1\1j-sv 0 C-rt, 2 h ls-sjs,v 0 C to rt NN) Cs2CO3, DMF, rt ==="¨N--......s.õ_,_)..._....,(1 OH
CI ¨dv.

1-6 -.....Cs'N
Br Pd(OAc)2, tricyclohexyl phosphine, K3PO4, toluene, H20, 90 C, 16 h N
[0142]
Synthesis of tert-butyl ((mesitylsulfonyl)oxy)carbamate. To a mixture of tert-butyl hydroxycarbamate (3 g, 22.5 mmol) and 2,4,6-trimethylbenzenesulfonyl chloride (4.9 g, 22.5 mmol) in MTBE (100 mL) was added Et3N (2.43 g, 24.0 mmol) at 0 C. The mixture was stirred at 0 C for 2 h. The reaction mixture was filtered and washed with MTBE. The filtrate was concentrated to give tert-butyl ((mesitylsulfonyl)oxy)carbamate (7.1 g, yield: 100%) as a light yellow solid. ESI-MS [M+Na]+: 338.1.
[0143] Synthesis of 0-(mesitylsulfonyl)hydroxylamine. The mixture of tert-butyl ((mesitylsulfonyl)oxy)carbamate (5.9 g, 18.71 mmol) in TFA (20 mL) was stirred for at 0 C for 2 h. The reaction mixture was poured into H20 (150 mL) and stirred for 30 min.
The precipitate was collected and dried to give 0-(mesitylsulfonyl)hydroxylamine (2.2 g, yield: 55%) as a white solid which was used into next step without further purification. ESI-MS
[M+H]+: 216.2.
[0144]
Synthesis of 5-cyclopropylpyridin-2-amine. The mixture of 5-bromopyridin-2-amine (4 g, 23.12 mmol), cyclopropylboronic acid (2.98 g, 34.68 mmol), Pd(OAc)2 (130 mg, 0.578 mmol), tricyclohexyl phosphine (324 mg, 1.16 mmol) and K3PO4 (17.18 g, 80.92 mmol) in toluene (100 mL) and H20 (10 mL) was stirred at 90 C for 16 h. The reaction mixture was filtered and rinsed with Et0Ac. The combined filtrate was washed with H20 (150 mL x 1) and brine (150 mL x 1), dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE = 1/1) to give 5-cyclopropylpyridin-2-amine (2.76 g, yield: 89%) as a yellow solid. ESI-MS [M+H]+: 135.2.
[0145] Synthesis of 5-cyclopropy1-2-iminopyridin-1(211)-amine 2,4,6-trimethylbenzenesulfonate. To a stirred solution of 0-(mesitylsulfonyl)hydroxylamine (2.2 g, 10.22 mmol) in DCM (40 mL) was added 5-cyclopropylpyridin-2-amine (1.37 g, 10.22 mmol) in four portions at 0 C. The mixture was stirred at 0 C for 10 min and warmed to RT and stirred for 1 h. The reaction mixture was concentrated and dried in vacuo to give 5-cyclopropy1-2-iminopyridin-1(2H)-amine 2,4,6-trimethylbenzenesulfonate (3.57 g, yield: 100%) as a light brown syrup. ESI-MS [M+H]+: 150.2.
[0146] Synthesis of ethyl 6-cyclopropy1-11,2,41triazolo11,5-alpyridine-2-carboxylate.
To a stirred solution of 5-cyclopropy1-2-iminopyridin-1(2H)-amine 2,4,6-trimethylbenzenesulfonate (3.57 g, 10.22 mmol) in pyridine (30 mL) was added ethyl 2-chloro-2-oxoacetate (2.79 g, 20.44 mmol) at RT. The mixture was stirred at 100 C for 16 h. The reaction mixture was concentrated. The residue was dissolved in Et0Ac (100 mL) and washed with H20 (100 mL x 1) brine (100 mL x 1), dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE = 1/1) to give ethyl 6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (1.1 g, yield: 47%) as a yellow solid. ESI-MS [M+H]+:
232.1.
[0147] Synthesis of (6-cyclopropy1-11,2,41triazolo11,5-alpyridin-2-y1)methanol. To a stirred solution of ethyl 6-cyclopropy141,2,4]triazolo[1,5-a]pyridine-2-carboxylate (300 mg, 1.30 mmol) in Me0H (10 mL) was added NaBH4 (246 mg, 6.5 mmol) in portions at 0 C.
The mixture was stirred at RT for 2 h. The reaction mixture was then quenched with NH4C1 aqueous.
Me0H was removed and the reaction was diluted with H20 (50 mL) and extracted with Et0Ac (30 mL x 3). The combined organics was washed with brine (80 mL x 1), dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/Me0H = 10/1) to give (6-cyclopropy141,2,4]triazolo[1,5-a]pyridin-2-yl)methanol (210 mg, yield: 85%) as a yellow solid.
ESI-MS [M+H]: 190.2.
[0148] Synthesis of 2-(chloromethyl)-6-cyclopropy1-11,2,41triazolo11,5-al pyridine. To a stirred solution of (6-cyclopropy141,2,4]triazolo[1,5-a]pyridin-2-yl)methanol (110 mg, 0.58 mmol) in DCM (5 mL) was added SOC12 (690 mg, 5.8 mmol) at 0 C. The mixture was stirred at RT for 1 h. The reaction mixture was then concentrated, the residue was dissolved in Et0Ac (60 mL) and washed with NaHCO3 (50 mL x 1), brine (50 mL x 1), dried over Na2SO4, concentrated to give 2-(chloromethyl)-6-cyclopropy141,2,4]triazolo[1,5-a]pyridine (115 mg, yield: 96%) as a yellow solid, which was used into next step without further purification. ESI-MS [M+H]: 208.1.
[0149] Synthesis of N4(7-chloroimidazo11,5-alpyridin-1-y1)methyl)-1-((6-cyclopropyl-11,2,41triazolo11,5-a]pyridin-2-yHmethyl)-1H-pyrazole-4-carboxamide (1-6).
The mixture of 2-(chloromethyl)-6-cyclopropy141,2,4]triazolo[1,5-a]pyridine (15.8 mg, 0.0762 mmol), N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (20 mg, 0.0725 mmol) and Cs2CO3 (35 mg, 0.109 mmol) in DIVIF (3 mL) was stirred at RT
for 2 h. The reaction mixture was poured into H20 (30 mL) and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine (60 mL x 3), dried over Na2SO4, concentrated and purified by prep-TLC (DCM/Me0H = 5/1) to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropy141,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (15 mg, yield: 47%) as a yellow solid. ESI-MS [M+H]: 447.1.
Purity: 99%. 111 NMR (400 MHz, DMS0): 6 8.73 (s, 1H), 8.62 (t, J = 5.7 Hz, 1H), 8.31 (d, J =
7.9 Hz, 3H), 7.86 (s, 1H), 7.80 (d, J = 0.9 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.42 (dd, J =
9.2, 1.7 Hz, 1H), 6.65 (dd, J = 7.5, 2.1 Hz, 1H), 5.56 (s, 2H), 4.57 (d, J = 5.7 Hz, 2H), 2.03 (m, 1H), 0.97 (m, 2H), 0.78 (m, 2H).
Example 7 Scheme 7 Cl Cl NH Ar NH / N
/01-I SOCl2 CI N CI 0 Ni)LtNN
1_7 N H
DCM Cs2CO3, DM F
[0150] Synthesis of 6-chloro-2-(chloromethyl)-5-methylimidazo11,2-al pyridine. To a solution (6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methanol (60 mg, 0.31 mmol) in DCM

(10 mL) was added SOC12 (I mL) at RT. The resulting reaction was stirred at 45 C for 2 h. The solution was evaporated to give the 6-chloro-2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (50 mg, crude) as a light yellow solid, which was used in the next step without further purification. ESI-MS [M+H]+: 215.2.
[0151] Synthesis of 1-((6-chloro-5-methylimidazo[1,2-alpyridin-2-y1)methyl)-N-((7-chloroimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1-7). To a solution 6-chloro-2-(chloromethyl)-5-methylimidazo [1,2-a]pyridine (50 mg, 0.23 mmol) in DIVIF (10 mL) was added N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (41 mg, 0.15 mmol) and Cs2CO3 (146 mg, 0.45 mmol) at RT. The resulting reaction was stirred at RT for 12 h. H20 (30 mL) was added to the reaction and then extracted with Et0Ac (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with prep-TLC (DCM/Me0H = 10/1) to give 14(6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (40 mg, yield: 58%) as a white solid. ESI-MS [M+H]+:
454.1. Purity:
100%. 111 NMR (400 MHz, DMS0): 6 8.59 (t, J = 5.5 Hz, 1H), 8.31-8.29 (m, 2H), 8.23 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.47 (d, J = 9.5 Hz, 1H), 7.34 (d, J
= 9.5 Hz, 1H), 6.65 (d, J = 7.4 Hz, 1H), 5.44 (s, 2H), 4.55 (d, J = 5.6 Hz, 2H), 2.66 (s, 3H).
Example 8 Scheme 8 ci IVH
j LtAIH4.11HF,... CLL.N_FH SOCI23DCM*N cs2c03 Dmi N
[0152] Synthesis of (7-isopropylimidazo11,2-a] pyridin-2-yl)methanol. To a solution of ethyl 7-isopropylimidazo[1,2-a]pyridine-2-carboxylate (200 mg, 0.86 mmol) in THF (4 mL) was added LiA1H4 (65.5 mg, 1.72 mmol). The resulting reaction was stirred at RT
for 4 h. The reaction was quenched with saturated Na2SO4(aq.), filtered and concentrated and purified by silica gel column (DCM/Me0H = 10/1) to give the (7-isopropylimidazo[1,2-a]pyridin-2-yl)methanol(130 mg, 80%) as a brown liquid. ESI-MS [M+H]+: 191.2.
[0153] Synthesis of 2-(chloromethyl)-7-isopropylimidazo11,2-al pyridine.
To a solution of (7-isopropylimidazo[1,2-a]pyridin-2-yl)methanol (190 mg, 1 mmol) in DCM (10 mL) was added SOC12 (2 mL). The resulting reaction was stirred at 50 C for 2 h.
The reaction was concentrate in vacuo to give 2-(chloromethyl)-7-isopropylimidazo[1,2-a]pyridine (220 mg crude), which was used into next step without further purification. ESI-MS
[M+H]+: 209.2.
[0154] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-isopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-8). A
mixture of 2-(chloromethyl)-7-isopropylimidazo[1,2-a]pyridine (46 mg, 0.22 mmol), N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (38 mg, 0.14 mmol) and Cs2CO3 (142 mg, 0.44 mmol) in DMF (8 mL) was stirred at 80 C for 12 h. H20 (15 mL) was added to the reaction, extracted with Et0Ac (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with prep-TLC (DCM/Me0H = 10/1) to give the N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-isopropylimidazo[1,2-a]pyridin-2-yOmethyl)-1H-pyrazole-4-carboxamide (15 mg, 24%) as a white solid. ESI-MS [M+H]+: 448.2. Purity: 100%. 111NMR (400 MHz, DMS0):
6 8.58 (t, J = 5.6 Hz, 1H), 8.32 (m, 3H), 8.20 (s, 1H), 7.85 (s, 1H), 7.77 (m, 2H), 7.43 (d, J = 9.3 Hz, 1H), 7.21 (d, J = 9.3 Hz, 1H), 6.64 (dd, J = 7.4, 1.9 Hz, 1H), 5.39 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 2.96-2.80 (m, 1H), 1.22 (d, J = 6.9 Hz, 6H).
Example 9 Scheme 9 .0 LAIH, NOH soci2 CI
H2N Et0H, zellux, 8 h I HI, 0 C. to rt. 5 h. DOA, 40 C, 1 h NAN\ -IcKi,;CZI-) vONNN
Cs2CO3. DMF rt. 16 h
[0155] Synthesis of (5-methylimidazo11,2-alpyridin-2-yl)methanol. A
solution of 5-chloro-6-methylpyridin-2-amine (568 mg, 4.0 mmol), ethyl 3-bromo-2-oxopropanoate (1.2 g, 6.0 mmol) in dry Et0H (10 mL) was stirred at 80 C for 8 h. The mixture was concentrated and purified by silica gel chromatography (DCM/Me0H = 20/1) to give ethyl 6-chloro-methylimidazo[1,2-a]pyridine-2-carboxylate (800 mg, yield: 84.0%) as a yellow solid. ESI-MS
[M+H]+: 239.1.
[0156] Synthesis of (5-methylimidazo11,2-alpyridin-2-yl)methanol. To a solution of ethyl 6-chloro-5-methylimidazo[1,2-a]pyridine-2-carboxylate (240 mg, 1.0 mmol) in dry THF
(10 mL) was added LiA1H4 (115 mg, 3.0 mmol) slowly at 0 C. The reaction mixture was stirred at RT for 5 h, then quenched with Na2SO4.10H20. The mixture was filtered and the filtrate was washed with Et0Ac (20 mL). The filtrate was concentrated to give (5-methylimidazo[1,2-a]pyridin-2-yl)methanol (150 mg, yield: 92%) as a yellow oil which was used in the next step without further purificaiton. ESI-MS [M+H]: 163.1.
[0157] Synthesis of 2-(chloromethyl)-5-methylimidazo11,2-al pyridine. To a solution of (5-methylimidazo[1,2-a]pyridin-2-yl)methanol (150 mg, 0.925 mmol) in dry DCM (5 mL) was added SOC12 (0.5 mL) at RT. The mixture was stirred at 40 C for 1 h. The mixture was concentrated to give crude 2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (140 mg, yield:
94.6%) as a yellow solid. ESI-MS [M+H]: 181.2.
[0158] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((5-methylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-9). A
mixture of 2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (30 mg, 0.16 mmol), N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (30 mg, 0.11 mmol) and Cs2CO3 (110 mg, 0.33 mmol) in DIVIF (3 mL) was stirred at RT for 16 h. Water (30 mL) was added and the reaction was extracted with Et0Ac (30 mL x 3). The combined organic layers were concentrated and purified by prep-TLC (DCM/Me0H = 10/1) to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-145-methylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (11.5 mg, yield: 25%) as a light yellow solid. ESI-MS
[M+H]: 420.1.
Purity: 97.4%. 111 NMR (400 MHz, DMS0): 6 8.58 (t, J = 5.4 Hz, 1H), 8.31-8.29 (m, 2H), 8.23 (s, 1H), 7.86 (s, 1H), 7.78 (s, 2H), 7.41 (d, J = 9.1 Hz, 1H), 7.24-7.20 (m, 1H), 6.78 (d, J = 6.8 Hz, 1H), 6.64 (dd, J = 7.5, 1.9 Hz, 1H), 5.43 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 2.56 (s, 3H).

Example 10 Scheme 10 y-o Zn(E02, TFA, CH212, N
DCM, 0 C to rt, 12 h 30,C1 ____________________ N-- Pd(dppO2C12, K3PO4 clioxane/H20, 115 C, 24 h CI

N CI
LAOH, THF/Me0H "====.
HON NH
H20, 70 C, 2 h 1\41e HATU, DIPEA, N
-N
[0159] Synthesis of ethyl 1-((6-(prop-1-en-2-yl)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. A mixture of ethyl 1-((6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (600 mg, 1.97 mmol), 4,4,5,5-tetramethy1-2-(prop-1-en-2-y1)-1,3,2-dioxaborolane (662 mg, 3.94 mmol), Pd(dppf)2C12 (160 mg, 0.2 mmol) and K3PO4 (1.25 g, 5.91 mmol) in dioxane/H20 (20 mL/2 mL) was stirred at 115 C for 24 h. H20 (50 mL) was added to the reaction, extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude, which was purified by prep-HPLC (chromatographic columns: Gemini-C18 150 x 21.2 mm, 5 um, mobile phase: acetonitrile-H20 (0.1%FA), gradient: 10-20) to give ethyl 146-(prop-1-en-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (450 mg, yield: 73%) as a white solid. ESI-MS [M+H]+: 311.2.
[0160] Synthesis of ethyl 1-((6-(1-methylcyclopropyl)imidazo11,2-alpyridin-y1)methyl)-1H-pyrazole-4-carboxylate. To a solution of Zn(Et)2 (1.9 mL, 1 M
solution in hexane, 1.9 mmol) in DCM (4 mL) was added TFA (220 mg, 1.9 mmol, in 1 mL DCM) dropwisely at 0 C. The resulting reaction was stirred at 0 C for 20 min.
Then a solution of CH2I2(509 mg, 1.9 mmol, in 2 mL DCM) was added at 0 C. After stirring for another 20 min, a solution of ethyl 14(6-(prop-1-en-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (50 mg, 0.16 mmol) in DCM (1 mL) was added. The resulting reaction was warmed to RT and stirred for 16 h. The reaction was quenched with H20 (20 mL) and extracted with DCM (25 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude, which was purified with prep-TLC
(DCM/Me0H =
15/1) to give ethyl 1-((6-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (17 mg, yield: 33%) as a yellow solid. ESI-MS [M+H]: 325.1.
[0161] Synthesis of 1-46-(1-methylcyclopropyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid. A mixture of ethyl 1-((6-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (17 mg, 0.052 mmol) and LiOH
(4 mg, 0.16 mmol) in THF/Me0H/H20 (2 mL/2 mL/1 mL) was stirred at 70 C for 2 h. The pH of the reaction was adjusted to 4 and H20 (5 mL) was added and the mixture was extracted with Et0Ac (20 mL x 3). The combined organic layers were then concentrated in vacuo to give the 14(6-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (15 mg, yield: 98%) as a yellow oil which was used in the next step without further purification. ESI-MS
[M+H]: 297.1.
[0162] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-46-(1-methylcyclopropyl)imidazo11,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-10).
To a solution of 1-((6-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (15 mg, 0.05 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (13 g, 0.06 mmol) and HATU (28 mg, 0.075 mmol) in DMF (3 mL) was added DIPEA (32 mg, 0.25 mmol). The resulting reaction was stirred at RT for 12 h.
H20 (15 mL) was added to the reaction and then extracted with Et0Ac (25 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentered in vacuo to give the crude, which was purified with prep-TLC (DCM/Me0H = 10/1) to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (7.5 mg, yield: 33%) as a white solid. ESI-MS [M+H]: 460.2.
Purity: 93.5%. 111 NMR (400 MHz, Me0D): 6 8.27-8.25 (m, 2H), 8.16 (d, J = 7.5 Hz, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.73-7.72 (m, 2H), 7.40 (d, J = 9.4 Hz, 1H), 7.26 (d, J = 9.4 Hz, 1H), 6.62 (d, J = 7.3 Hz, 1H), 5.44 (s, 2H), 4.68 (s, 2H), 1.41 (s, 3H), 0.90-0.87 (m, 2H), 0.78-0.76 (m, 2H).

Example 11 Scheme 11 N

CI CI fe...) `r 0 Cs2CO3 N NH2 Et0H, 80 C, 4 h DMF, rt, 2 h CI
[0163] Synthesis of 6-chloro-2-(chloromethyl)imidazo11,2-131pyridazine. A
solution of 6-chloropyridazin-3-amine (5 g, 39 mmol) and 1, 3-dichloropropan-2-one (20 g, 156 mmol) in Et0H (50 mL) was stirred at 90 C for 4 h. Then the reaction mixture was diluted with H20 (100 mL) and extracted with Et0Ac (100 mL x 3). The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography (PE/EA = 5/1) to give the desired product 6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (2.6 g, yield: 33%) as a yellow solid. ESI-MS [M+H]+: 202.2.
[0164] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-131pyridazin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-11). A
solution of 6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (50 mg, 0.25 mmol), N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (66 mg, 0.24 mmol), Cs2CO3(160 mg, 0.5 mmol) in DMF (3 mL) was stirred at RT for 2 h. Then the reaction mixture was diluted with H20 (30 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography (CH2C12/Me0H = 10/1) to give the desired compound N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1H-pyrazole-4-carboxamide (29.5 mg, yield: 27%) as a white solid. ESI-MS [M+H]+: 441.1. Purity: 98%.
IIINNIR (400 MHz, DMS0): 6 8.58 (s, 1H), 8.31 (s, 3H), 8.25 (s, 1H), 8.17 (d, J= 9.3 Hz, 1H), 7.86 (s, 1H),7.78 (s, 1H), 7.38 (d, J = 9.5 Hz, 1H), 6.65 (d, J = 7.1 Hz, 1H), 5.47 (s, 2H), 4.56 (d, J = 5.0 Hz, 2H).

Example 12 Scheme 12 o ---- N--) __ ill SOCI 2, DCM v...,C)..._ Li0H, THF/Me0H
N.D.,Ir "-- 4, rt, 3 h Cs2CO3, DMF
H20, 80 C, 2 h rt, 12 h 0 ......)....

ve..C1i....\I¨)_\
N N
NIOH ,_ 43,1-1...Q
HATU, DIPEA
0 DMF, rt, 2 h 1-12 0 0¨
[0165] Synthesis of 2-(chloromethyl)-7-cyclopropylimidazo11,2-al pyridine. To a solution of (7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol (126 mg, 0.67 mmol) in DCM
(10 mL) was added SOC12 (2 mL). The resulting reaction was stirred at 45 C
for 4 h. The reaction was concentrated in vacuo to give the 2-(chloromethyl)-7-cyclopropylimidazo[1,2-a]pyridine (150 mg crude), which was used in the next step without further purification. ESI-MS
[M+H]+: 207.2.
[0166] Synthesis of ethyl 14(7-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-111-pyrazole-4-carboxylate. A mixture of 2-(chloromethyl)-7-cyclopropylimidazo[1,2-a]pyridine (0.15 g crude from previous step), ethyl 1H-pyrazole-4-carboxylate (126 mg, 0.9 mmol) and Cs2CO3 (1.17 g, 3.6 mmol) in DMF (8 mL) was stirred at 80 C for 12 h. H20 (15 mL) was added to the reaction and then extracted with Et0Ac (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with prep-TLC (DCM/Me0H = 10/1) to give ethyl 1-((7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (100 mg, 36%) as a yellow solid. ESI-MS
[M+H]+: 311.2.
[0167] Synthesis of 14(7-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-pyrazole-4-carboxylic acid. A mixture of ethyl 1-((7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (600 mg, 1.94 mmol) and LiOH (270 mg, 11.6 mmol) in THF/Et0H/H20 (6 mL/6 mL/4 mL) was stirred at 80 C for 2 h. The pH of reaction was adjusted to around 5 and a yellow solid was precipitated out. The mixture was filtered and the solid was dried to give 1((7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (550 mg, yield: 100%) as a brown solid. ESI-MS [M+H]+: 283.1.
[0168] Synthesis of 1-((7-cyclopropylimidazo[1,2-alpyridin-2-yl)methyl)-N-((6-methoxyimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-12). To a solution of 1((7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (23 mg, 0.08 mmol), (7-methoxyimidazo[1,5-a]pyridin-1-yl)methanamine (14 mg, 0.08 mmol) and HATU (45.6 mg, 0.12 mmol) in DMF (3 mL) was added DIPEA (30 mg, 0.24 mmol). The resulting reaction stirred at RT for overnight. H20 (20 mL) was added to the reaction and then extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude, which was purified with prep-TLC
(DCM/Me0H = 10/1) to give 14(7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((6-methoxyimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (30 mg, yield: 85%).
ESI-MS [M+H]: 442.1. Purity: 98.3%. lEINIVIR (400 MHz, Me0D): 6 8.22 (s, 1H), 8.15 (s, 1H), 8.12 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.94 (s, 1H), 7.73 (s, 1H), 7.41 (d, J = 9.4 Hz, 1H), 7.14 (d, J = 9.4 Hz, 1H), 6.90 (s, 1H), 6.41 (dd, J = 7.6, 2.2 Hz, 1H), 5.46 (s, 2H), 4.69 (s, 2H), 3.81 (s, 3H), 2.05-1.83 (m, 1H), 1.07-0.92 (m, 2H), 0.86-0.63 (m, 2H).
Example 13 Scheme 13 BrO
11\ 0 LiAiH4, THF
Nfli_ JOH
H, Et0H, reflux, 16 h ¨\ 0 C to rt, 1 h 3w.
1514\1\;1---L\)ON

DCM 7Cs2CO3, DMF, 50 C, 2 h
[0169] Synthesis of ethyl 6-cyclopropy1-5-methylimidazo[1,2-a] pyridine-2-carboxylate. A mixture of 5-cyclopropy1-6-methylpyridin-2-amine (1.3 g, 8.78 mmol), ethyl 3-bromo-2-oxopropanoate (3.5 g, 17.57 mmol) in Et0H (30 mL) was stirred at 90 C
for 16 h. The mixture was concentrated and purified by silica gel chromatography (DCM/Me0H =
20/1) to give ethyl 6-cyclopropy1-5-methylimidazo[1,2-a]pyridine-2-carboxylate (150 mg, yield: 7%) as a yellow solid. ESI-MS [M+H]+: 245.1.
[0170] Synthesis of (6-cyclopropy1-5-methylimidazo11,2-alpyridin-2-y1)methanol. To a solution of ethyl 6-cyclopropy1-5-methylimidazo[1,2-a]pyridine-2-carboxylate (110 mg, 0.45 mmol) in dry THF (5 mL) was added LiA1H4 (50 mg, 1.12 mmol) slowly at 0 C.
After the mixture was stirred at RT for 1 h, it was quenched with Na2SO4.10H20. The mixture was filtered and the filtrate was washed with Et0Ac (20 mL). The filtrate was concentrated and purified by prep-TLC (DCM/Me0H = 15/1) to give (6-cyclopropy1-5-methylimidazo[1,2-a]pyridin-2-y1) methanol (50 mg, yield: 55%) as a yellow solid. ESI-MS [M+H]+: 203.1.
[0171] Synthesis of 2-(chloromethyl)-6-cyclopropy1-5-methylimidazo11,2-al pyridine.
To a solution of (6-cyclopropy1-5-methylimidazo[1,2-a]pyridin-2-yl)methanol (50 mg, 0.25 mmol) in dry DCM (2.5 mL) was added SOC12 (0.5 mL) at RT. The mixture was stirred at 40 C
for 1 h. The mixture was concentrated to give 2-(chloromethyl)-6-cyclopropy1-5-methylimidazo [1,2-a]pyridine (50 mg, yield: 90.9%) as a yellow oil. which was used in the next step without further purification. ESI-MS [M+H]: 221.2.
[0172] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropyl-5-methylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-13). A mixture of 2-(chloromethyl)-6-cyclopropy1-5-methylimidazo[1,2-a]pyridine (25 mg, 0.11 mmol), N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (30 mg, 0.11 mmol) and Cs2CO3 (110 mg, 0.33 mmol) in DIVIF (3 mL) was stirred at 50 C
for 2 h. Water (20 mL) was added and extracted with Et0Ac (20 mL x 3). The combined organic layers were concentrated and purified by prep-TLC (DCM/Me0H = 10/1) to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (17 mg, yield: 33.7%) as a light yellow solid. ESI-MS
[M+H]: 460.2.
Purity: 99.5%. 111 NMR (400 MHz, DMS0): 6 8.57 (s, 1H), 8.30 (d, J = 7.1 Hz, 2H), 8.20 (s, 1H), 7.85 (s, 1H), 7.77 (s, 2H), 7.33 (d, J = 9.6 Hz, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.64 (d, J = 7.3 Hz, 1H), 5.40 (s, 2H), 4.54 (d, J = 5.1 Hz, 2H), 2.64 (s, 3H), 2.02 (s, 1H), 0.94 (d, J = 8.2 Hz, 2H), 0.64 (s, 2H).
Example 14 Scheme 14 H,N
A r Cs2CO3, DNIF, 50 C,211 icliN 0 H H,0 0H HATU. DIPEA, DMF, 2 h \--C-14aTN
r/ C
[0173] Synthesis of ethyl 1-((6-cyclopropy1-5-methylimidazo11,2-alpyridin-y1)methyl)-1H-pyrazole-4-carboxylate. A mixture of 2-(chloromethyl)-6-cyclopropy1-5-methylimidazo[1,2-a]pyridine (65 mg, 0.30 mmol), ethyl 1H-pyrazole-4-carboxylate (45 mg, 0.32 mmol) and Cs2CO3 (245 mg, 0.75 mmol) in DMF (5 mL) was stirred at 50 C
for 2 h.
Water (20 mL) was added and extracted with Et0Ac (20 mL x 3). The combined organic layers were concentrated to give ethyl 14(6-cyclopropy1-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (65 mg, yield: 67%) as a yellow solid. ESI-MS
[M+H]+: 325.1.
[0174] Synthesis of 1-((6-cyclopropy1-5-methylimidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid. A solution of ethyl 1-((6-cyclopropy1-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (65 mg, 0.2 mmol) and Li0E14-120 (25 mg, 0.6 mmol) in THF/Me0H/H20 (1 mL/1 mL/0.5 mL) was stirred at 80 C for 1 h. The pH of the mixture was adjusted to 4 by adding 1 M HC1 solution. Water (10 mL) was added and the reaction was extracted with Et0Ac (20 mL x 3).The combined organic layers were concentrated to give 1-((6-cyclopropy1-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (59 mg, yield: 99.7%) as a yellow oil. which was used directly in the next step without further purification. ESI-MS [M+H]: 297.1.
[0175] Synthesis of N-((7-bromoimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropyl-5-methylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-14). A mixture of 1-((6-cyclopropy1-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (59 mg, 0.2 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine (70 mg, 0.25 mmol), HATU (120 mg, 0.3 mmol) and DIPEA (0.1 mL, 0.6 mmol) in DMF (4 mL) was stirred at RT for 2 h. Water (20 mL) was added and the reaction was extracted with Et0Ac (30 mL x 3). The organic layers were concentrated and purified by prep-TLC
(DCM/Me0H = 10/1) to give N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (42.2 mg, yield: 41.9%) as a white solid.
ESI-MS [M+H]: 504.1. Purity: 93.5%. 1E1 NMR (400 MHz, DMS0): 6 8.57 (t, J =
5.7 Hz, 1H), 8.31 (s, 1H), 8.27-8.17 (m, 2H), 7.94 (s, 1H), 7.85 (s, 1H), 7.77 (s, 1H), 7.33 (d, J = 9.3 Hz, 1H), 6.97 (d, J = 9.3 Hz, 1H), 6.71 (dd, J = 7.4, 1.9 Hz, 1H), 5.41 (s, 2H), 4.54 (d, J = 5.7 Hz, 2H), 2.64 (s, 3H), 2.01-1.98 (m, 1H), 0.94 (dd, J = 8.4, 1.7 Hz, 2H), 0.74-0.58 (m, 2H).
Example 15 Scheme 15 0)_r NIV-.--N, 'OH
10)1'0"---N
Cin 0CICI cs,c03 CINN
Pd(OAC)2. SPhos. 1(31'04..
N NH, Et0H, 80 C. 4 h DMF. rt. 2 h Toluene/H20. 90 C. 2 h LOH
N
THF/Et0H/H,0. HOBt. EDCI, TEA. 0 80C. 2 h DCM. rt. (nernight I-I5 CI
[0176] Synthesis of 6-chloro-2-(chloromethyl)imidazo[1,2-131pyridazine. A
solution of 6-chloropyridazin-3-amine (20.0 g, 155.0 mmol) and 1,3-dichloropropan-2-one (49.2 g, 387.5 mmol) in Et0H (200 mL) was stirred at 80 C for 4 h. Then the reaction mixture was concentrated and diluted with H20 (300 mL x 3) and extracted with Et0Ac (500 mL x 3). The combined organic layer were dried over Na2SO4, concentrated and purified by column chromatography (DCM: Me0H = 10: 1) to give the desired product 6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (17.0 g, yield: 54%) as a yellow solid.
ESI-MS [M+H]+:
202.1.
[0177] Synthesis of ethyl 1-((6-chloroimidazo11,2-131pyridazin-2-y1)methyl)-111-pyrazole-4-carboxylate. A solution of 6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (10.0 g, 49.5 mmol), ethyl 1H-pyrazole-4-carboxylate (6.2 g, 44.5 mmol), Cs2CO3 (48.4 g, 148.5 mmol) in DMF (200 mL) was stirred at RT for 2 h. Most of the DNIF was concentrated, the residue was diluted with H20 (300 mL) and extracted with Et0Ac (500 mL x 3).
The combined organic layer were dried over Na2SO4, concentrated and purified by column chromatography (Et0Ac:PE = 2:1) to give the desired compound ethyl 14(6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylate (10.0 g, yield: 65%) as a yellow solid, ESI-MS [M+H]:
306.1.
[0178] Synthesis of methyl 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylate. A solution of ethyl 14(6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylate (10.0 g, 32 mmol) , cyclopropylboronic acid (4.2 g, 49 mmol), Pd(OAc)2 (718.4 mg, 3.2 mmol) , SPhos (1.3 g, 3.2 mmol) and K3PO4(21.0 g, 96 mmol) in Tol/H20 (100 mL/10 mL) was stirred at RT for 2 h. Then the reaction mixture was diluted with H20 (100 mL) and extracted with Et0Ac (300 mL x 3). The combined organic layer were dried over Na2SO4, concentrated and purified by column chromatography (Et0Ac:PE = 2:1) to give the desired compound ethyl 14(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylate (9.8 g, yield: 100%) as a white solid. ESI-MS [M+H]:
312.2.
[0179] Synthesis of 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-pyrazole-4-carboxylic acid. A solution of ethyl 14(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylate (9.8 g, 32.0 mmol) and LiOH (1.5 g, 64.0 mmol) in THF/Et0H/H20 (80 mL/80 mL/80 mL) was stirred at 80 C for 2 h. Then the reaction mixture was concentrated and diluted with H20 (50 mL). The pH of the solution was adjusted to 5 by adding 1 M HC1 solution. Solid precipitated and was filtered to give the desired compound 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (9.5 g, yield:
104.6%) as a white solid. ESI-MS [M+H]: 284.1.
[0180] Synthesis of N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-15). A
solution of 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (9.5 g, 33.5 mmol) , (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (9.5 g, 43.5 mmol), EDCI (7.7 g, 40.2 mmol), HOBT (5.4 g, 40.2 mmol) and TEA (10.1 g, 13.9 mL, 100.5 mmol) in dry DCM (800 mL) was stirred at RT overnight. Then the reaction mixture was diluted with H20 (500 mL x 3) and extracted with DCM (1 L x 3). The combined organic layer were dried over Na2SO4,concentrated and purified by column chromatography (DCM: Me0H = 10: 1) to give the desired compound N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1H-pyrazole-4-carboxamide (6.1 g, yield:
40.9%) as a white solid. ESI-MS [M+H]: 447.1. Purity: 99.05%. IENNIR (400 MHz, DMS0):
6 8.58-8.55 (t, J = 5.7 Hz, 1H), 8.30-8.28 (m, J = 7.5, 0.6 Hz, 2H), 8.21 (s, 1H), 8.07 (s, 1H), 7.91 (d, J = 9.5 Hz, 1H), 7.84 (s, 1H), 7.77-7.76 (m, 1H), 7.08 (d, J = 9.5 Hz, 1H), 6.63 (dd, J =
7.5, 2.1 Hz, 1H), 5.40 (s, 2H), 4.54 (d, J = 5.7 Hz, 2H), 2.50-2.14 (m, J =
9.0, 4.1 Hz, 1H), 1.07-1.03 (m, J = 6.0, 4.1 Hz, 2H), 0.97-0.93 (m, 2H).
Example 16 Scheme 16 CI

NH, CI
/CY
Pd(OAc)2, SPhos DME
Cs2CO3, DME N 11\11krNir---4 Br
[0181] Synthesis of 5-cyclopropy1-4-methylpyridin-2-amine. To a solution of 5-bromo-4-methylpyridin-2-amine (2 g, 10.7 mmol) in toluene/H20 (50 mL/5 mL) was added cyclopropylboronic acid (1.36 g, 16.0 mmol), Pd(OAc)2 (240 mg, 1.07 mmol), SPhos (439 mg, 1.07 mmol) and K3PO4 (6.8 g, 32.1 mmol). The reaction mixture was stirred at 95 C for 12 h under nitrogen, then diluted with DCM (200 mL), washed with H20 and brine, and concentrated to give the crude residue which was purified by silica gel chromatography (PE/Et0Ac = 1/1) to afford 5-cyclopropy1-4-methylpyridin-2-amine as a yellow solid (4 g, yield:
90%). ESI-MS
[M+H]+: 149.2.
[0182] Synthesis of 2-(chloromethyl)-6-cyclopropy1-7-methylimidazo11,2-al pyridine.
To a solution 5-cyclopropy1-4-methylpyridin-2-amine (200 mg, 1.35 mmol) in DIVIF (10 mL) was added 1,3-dichloropropan-2-one (514 mg, 4.05 mmol) at RT. The resulting reaction was stirred at 85 C for 2 h. The solution was quenched with H20 (30 mL), adjusted to pH 8 by adding saturated NaHCO3 solution, and then extracted with Et0Ac (30 mL x 3).
The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude, which was purified by prep-TLC (PE/Et0Ac = 1/1) to give the 2-(chloromethyl)-6-cyclopropy1-7-methylimidazo[1,2-a]pyridine (150 mg, yield: 51%) as a light yellow oil. ESI-MS
[M+H]+: 221.2.
[0183] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-((6-cyclopropyl-7-methylimidazo11,2-alpyridin-2-yHmethyl)-1H-pyrazole-4-carboxamide (I-17). To a solution 2-(chloromethyl)-6-cyclopropy1-7-methylimidazo[1,2-a]pyridine (55 mg, 0.25 mmol) in DMF (4 mL) was added N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (45 mg, 0.16 mmol) and Cs2CO3 (156 mg, 0.48 mmol) at RT. The resulting reaction was stirred at RT for 12 h. H20 (20 mL) was added to the reaction and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified by prep-TLC
(DCM/Me0H = 10/1) to give the N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-methylimidazo[1,2-a]pyridine-2-y1)methyl)-1H-pyrazole-4-carboxamide (20 mg, yield: 27%) as a white solid. ESI-MS [M+H]+: 460.1. 11-1NMR (400 MHz, DMS0): 6 8.58 (t, J =
5.7 Hz, 1H), 8.35-8.27 (m, 2H), 8.23 (s, 1H), 8.19 (s, 1H), 7.86 (s, 1H), 7.79-7.74 (m, 1H), 7.66 (s, 1H), 7.30 (s, 1H), 6.66-6.63 (m, 1H), 5.38 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 2.42 (s, 3H), 1.88-1.82 (m, 1H), 0.94-0.84 (m, 2H), 0.62-0.54 (m, 2H).
Example 17 Scheme 17 Br Br N)C--CNNH

Cs2CO3, DMF H
[0184] Synthesis of N-((7-bromoimidazo11,5-alpyridin-1-yl)methyl)-1-((6-cyclopropyl-7-methylimidazo11,2-alpyridin-2-yHmethyl)-1H-pyrazole-4-carboxamide (I-17). To a solution of 2-(chloromethyl)-6-cyclopropy1-7-methylimidazo[1,2-a]pyridine (50 mg, 0.23 mmol) in DMF (4 mL) was added N4(7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (48 mg, 0.15 mmol) and Cs2CO3(147 mg, 0.45 mmol) at RT.
The resulting reaction was stirred at RT for 12 h. the reaction was quenched with H20 (20 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified by prep-TLC
(DCM/Me0H = 10/1) to give the N4(7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-methylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (22 mg, yield: 29%) as a white solid. ESI-MS [M+H]+: 506.1. Purity: 91.6%. lEINMR (400 MHz, DMS0): 6 8.58-8.55 (m, 1H), 8.31 (s, 1H), 8.24 (d, J = 7.4 Hz, 1H), 8.19-8.17 (m, 2H), 7.95 (s, 1H), 7.84 (s, 1H), 7.62 (s, 1H), 7.26 (s, 1H), 6.73-6.70 (m, 1H), 5.35 (s, 2H), 4.54 (d, J = 5.7 Hz, 2H), 2.40 (s, 3H), 1.85-1.81 (m, 1H), 0.89-0.87 (m, 2H), 0.58-0.56 (m, 2H).
Example 18 Scheme 18 N

CF3 C1)-C1 F3C CI

H2N DMF, 95 C, 13 h Cs2CO3, DMF
55 C, 2 h \N N
[0185] Synthesis of 2-(chloromethyl)-6-(trifluoromethyl)imidazo11,2-al pyridine. A
solution of 5-(trifluoromethyl)pyridin-2-amine (500 mg, 3.1 mmol) and 1,3-dichloropropan-2-one (1.2 g, 9.3 mmol) in DIVIF (15 mL) was stirred at 95 C for 13 h. The reaction was quenched with aqueous NaHCO3 solution (20 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel chromatography (PE/EA = 1/2) to give the 2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (350 mg, yield: 48%) as a yellow solid. ESI-MS [M+H]+: 235.2.
[0186] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-46-(trifluoromethyl)imidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-18). A
mixture of 2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (200 mg, 0.85 mmol), N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (234 mg, 0.85 mmol) and Cs2CO3 (831 mg, 2.55 mmol) in DMF (10 mL) was stirred at 55 C for 2 h.
H20 (30 mL) was added to the reaction and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified by prep-TLC (DCM/Me0H = 10/1) to give the N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (25 mg, yield: 6.2%) as a white solid. ESI-MS [M+H]: 474.2.
Purity: 99.7%. 111 NMR (400 MHz, Me0D): 6 8.99 (s, 1H), 8.27 (s, 1H), 8.19-8.17 (m, 2H), 7.93 (s, 2H), 7.75 (s, 1H), 7.66 (d, J = 9.5 Hz, 1H), 7.50 (dd, J = 9.5, 1.5 Hz, 1H), 6.63 (dd, J =
7.5, 1.9 Hz, 1H), 5.52 (s, 2H), 4.70 (s, 2H).
Example 19 Scheme 19 NN
N
F3CN,.% FC 0 Br N N";\
T\
N Cs2CO3, DMF
55 C, 2 h 1-19 0 Br
[0187] Synthesis of N-((7-bromoimidazo11,5-alpyridin-1-yl)methyl)-1-06 (trifluoromethyl)imidazo[1,2-alpyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-19). A
mixture of 2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (200 mg, 0.85 mmol), N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (271 mg, 0.85 mmol) and Cs2CO3 (831 mg, 2.55 mmol) in DMF (10 mL) was stirred at 55 C for 2 h.
H20 (30 mL) was added to the reaction and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified by prep-TLC (DCM/Me0H = 10/1) to give the N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (40 mg, yield: 9%) as a white solid. ESI-MS [M+H]+: 518Ø Purity:
94.14%. 11-1 NMR (400 MHz, Me0D): 6 8.99 (s, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 8.11 (d, J =
7.4 Hz, 1H), 7.94 (s, 3H), 7.66 (d, J = 9.5 Hz, 1H), 7.50 (d, J = 9.5 Hz, 1H), 6.75-6.67 (m, 1H), 5.52 (s, 2H), 4.70 (s, 2H).
Example 20 Scheme 20 0 )L0 N
H2NF Pd(Ac0)2. PCY 3 DME. 95 C. 13 h Cs2CO3. DME
K3PO4. toluene/H20 HN 55 C, 2 h 12h, 105 C

LION, THF/Me0H/H20 ""N N N N N
10--.1,0,../ 80 C. 1.5 h 40H HATU, DIPEA N.õ)----Q
DME. rt, 2 h Br
[0188] Synthesis of 5-cyclopropy1-4-fluoropyridin-2-amine. A mixture of 5-bromo-4-fluoropyridin-2-amine (1 g, 5.2 mmol), cyclopropylboronic acid (675 mg, 7.9 mmol), Pd(Ac0)2 (116 mg, 0.52 mmol), PCy3 (280 mg, 1 mmol) and K3PO4 (3.3 g, 15.6 mmol) in toluene/H20 (50 mL/5 mL) was stirred in a sealed tube at 105 C under N2 for 12 h. The reaction was concentrated to give the crude, which was purified by silica gel chromatography (PE/EA = 1/1) to give the 5-cyclopropy1-4-fluoropyridin-2-amine (500 mg, yield: 64%) as a white solid. ESI-MS [M+H]+: 153.2.
[0189] Synthesis of 2-(chloromethyl)-6-cyclopropy1-7-fluoroimidazo11,2-al pyridine.
A mixture of 5-cyclopropy1-4-fluoropyridin-2-amine (500 mg, 3.3 mmol) and 1,3-dichloropropan-2-one (1.25 g, 9.9 mmol) in DMF (30 mL) was stirred at 95 C
for 13 h. The pH
of the reaction was adjusted to 9 by addition of aqueous NaHCO3 and then extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude, which was purified with silica gel chromatography (PE/EA = 3/1) to give the 2-(chloromethyl)-6-cyclopropy1-7-fluoroimidazo[1,2-a]pyridine (150 mg, yield: 20%) as a yellow solid. ESI-MS [M+H]+: 225.1.
[0190] Synthesis of ethyl 1-((6-cyclopropy1-7-fluoroimidazo11,2-alpyridin-y1)methyl)-1H-pyrazole-4-carboxylate. A mixture of 2-(chloromethyl)-6-cyclopropy1-7-fluoroimidazo[1,2-a]pyridine (150 mg, 0.67 mmol), ethyl 1H-pyrazole-4-carboxylate (103 mg, 0.74 mmol) and Cs2CO3 (655 mg, 2.01 mmol) in DNIF (10 mL) was stirred at 55 C
for 2 h. H20 (30 mL) was added to the reaction and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/Me0H = 20/1) to give the ethyl 1-((6-cyclopropy1-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (100 mg, yield: 45%) as yellow solid. ESI-MS [M+H]+: 329.2.
[0191] Synthesis of 1-((6-cyclopropy1-7-fluoroimidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl 1-((6-cyclopropy1-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (100 mg, 0.31 mmol) in THF/Et0H/H20 (4 mL/4 mL/2 mL) was added LiOH (22 mg, 0.91 mmol). The resulting reaction was stirred at 80 C for 1.5 h. Most of the solvent was removed. The pH of the residue was adjusted to around 5 and a yellow solid was precipitate out. The mixture was filtered and the solid was dried to give the 1-((6-cyclopropy1-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (75 mg, yield: 81%) as a yellow solid. ESI-MS [M+H]+: 301.1.
[0192] Synthesis of N-((7-bromoimidazo11,5-alpyridin-1-yl)methyl)-1-((6-cyclopropyl-7-fluoroimidazo11,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-20).
To a solution of 1-((6-cyclopropy1-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (35 mg, 0.12 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine (35 mg, 0.15 mmol) and HATU (68 mg, 0.18 mmol) in DMF (5 mL) was added DIPEA (77 mg, 0.6 mmol). The resulting reaction was stirred at RT for 2 h. Water (30 mL) was added and extracted with Et0Ac (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with prep-TLC
(DCM/Me0H = 10/1) to give N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (19 mg, yield: 32%). ESI-MS [M+H]+: 508.1. Purity: 90.5%. IENNIR (400 MHz, Me0D): 6 8.26 (s, 1H), 8.18 (d, J = 7.1 Hz, 1H), 8.13 (s, 1H), 8.10 (d, J = 7.4 Hz, 1H), 7.92 (s, 1H), 7.91 (s, 1H), 7.67 (s, 1H), 7.12 (d, J = 10.3 Hz, 1H), 6.72 (d, J = 7.4 Hz, 1H), 5.41 (s, 2H), 4.68 (s, 2H), 2.04-1.87 (m, 1H), 1.02-0.97 (m, 2H), 0.76-0.72 (m, 2H).

Example 21 Scheme 21 ci H NN
N N
\ OH HATU, DIPEA N
DMF, rt, 2 h 1-21 CI
[0193] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yHmethyl)-1H-pyrazole-4-carboxamide (I-21).
To a solution of 1-((6-cyclopropy1-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (35 mg, 0.12 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (28 mg, 0.15 mmol) and HATU (68 mg, 0.18 mmol) in DMF (5 mL) was added DIPEA (77 mg, 0.6 mmol). The resulting reaction was stirred at RT for 2 h. Water (30 mL) was added and extracted with Et0Ac (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with prep-TLC
(DCM/Me0H = 10/1) to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (20 mg, yield: 32%). ESI-MS [M+H]+: 464.1. Purity: 94.8%. IENNIR (400 MHz, Me0D): 6 8.25 (s, 1H), 8.19-8.12 (m, 3H), 7.90 (s, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.13 (d, J =
10.3 Hz, 2H), 6.62 (dd, J = 7.5, 1.9 Hz, 1H), 5.41 (s, 2H), 4.68 (s, 2H), 1.37 (dd, J = 6.7, 3.3 Hz, 1H), 1.02-0.97 (m, 2H), 0.75-0.71 (m, 2H).

Example 22 Scheme 22 1), B2H
µOH 0 0 0 ND-4, Pd(Ac0)2, SPhos. K.311104 N NH2 Ntyk 0----N
Toluene/H20, 90 C, 18h I DMP. 80 C, 2 5 h Cs2CO3. DMP. rt, 3 h --1=1 Li0h1.1-120 h N4.syksoil HATU, DIPEA NN
H20/Et0H/THF. --)_/N DMP. rt, 18 h =-=&11¨"N
80 C, 1 5 --1=1 1-22
[0194] Synthesis of 6-cyclopropylpyridin-2-amine. To a solution of 2-amino-6-bromopyridine (1.0 g, 5.75 mmol) in toluene/H20 (15 mL/3 mL) was added cyclopropylboronic acid (1.98 g, 23 mmol), Palladium diacetate (134 mg, 0.63 mmol), 2-dicyclohexylphosphino-2', 6-dimethoxybihenyl (240 mg, 0.6 mmol) and potassium phosphate (4.24 g, 20.12 mmol). The resulting mixture was stirred at 90 C for 16 h. The reaction was diluted with H20 (20 mL), extracted with ethyl acetate (3 x 50 mL), The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give 6-cyclopropylpyridin-2-amine (621 mg, yield: 81%). ESI-MS [M+H]+:
135.2.
[0195] Synthesis of 2-(chloromethyl)-5-cyclopropylimidazo[1,2-a]pyridine.
To a solution of 5-cyclopropylpyrimidin-2-amine (600 mg, 4.5 mmol) in N,N-dimethylformamine (2 mL) was added 1,3-dichloropropan-2-one (2.2 g, 18.0 mmol).The resulting mixture was stirred at 80 C for 2.5 h. The reaction mixture was quenched with H20 (50 mL) and extracted with ethyl acetate (3 x 30 mL), The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give 2-(chloromethyl)-5-cyclopropylimidazo[1,2-a]pyridine (300 mg, yield:
33%). ESI-MS
[M+H]+: 207.1.
[0196] Synthesis of ethyl 1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-111-pyrazole-4-carboxylate. To a solution of 2-(chloromethyl)-5-cyclopropylimidazo[1,2-a]pyridine (150 mg, 0.73 mmol) in N,N-dimethylformamine (2 mL) was added cesium carbonate (949 mg, 2.92 mmol) and ethyl 1H-pyrazole-4-carboxylate (102 mg, 0.73 mmol). The resulting mixture was stirred at RTfor 3 h. Water (50 mL) was added and extracted with ethyl acetate (3 x 30 mL).
The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give ethyl 14(5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (220 mg, yield:
80%). ESI-MS [M+H]+: 311.2.
[0197] Synthesis of 1-((5-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-pyrazole-4-carboxylic acid. To a solution of ethyl 145-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (210 mg, 0.68 mmol) in a mixture solvent of THF/Et0H/H20 (3 mL/3 mL/1.5 mL) was added lithium hydroxide (82 mg, 3.39 mmol). The resulting mixture was stirred at 80 C for 1.5 h. Water (50 mL) was added and the pH of the mixture was adjusted to 4-5 by adding HC1 solution. The mixture was then extracted with DCM
(3 x 30 mL), The organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 145-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (140 mg, Yield: 60%) which was used in the next step without further purification. ESI-MS [M+H]+: 283.1.
[0198] Synthesis of N-((7-chloroimidazo11,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-22). To the solution of 1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (67 mg, 0.21 mmol) in dry DMF (3 mL) was added HATU(116 mg, 0.305 mmol), DIPEA
(16 mg, 0.125 mmol) and (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (44 mg, 0.24 mmol) at RT. The reaction was stirred at RT for 2 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-HPLC
to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-145-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (36 mg, yield: 30%) as a white solid.
ESI-MS [M+H]:
446.2. Purity: 98.74. 111 NMR (400 MHz, DMS0): 6 8.59 (t, J = 5.6 Hz, 1H), 8.34-8.26 (m, 2H), 8.25 (s, 1H), 8.02 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H)., 7.24-7.14 (m, 1H), 6.72-6.61 (m, 2H), 5.45 (s, 2H), 4.55 (d, J = 5.8 Hz, 2H), 2.18 (s, 1H), 1.13-1.1.02 (m, 2H), 0.83-0.74 (mõ 2H).

Example 23 Scheme 23 Br ci [>-13(OH)2 ci N Pd(OAc)2. EC) K3PO4 ,,N,, N
H2N (hexa, Hne ,0 I00 C. 16 h .. H,N _ Et0H, 80C.16 h Cs2C103. DMF. 55 C. 16 h NH, HCI
,N
DOH H,0 N HATE, DIEA H
_____ r THF/H20, rt. 16h OH DMF. rt. 16h 1-23 CI
[0199] Synthesis of 6-chloro-5-cyclopropylpyridin-2-amine. A mixture of 5-bromo-6-chloropyridin-2-amine (3 g, 14 mmol) and cyclopropyl boronic acid (2.4 g, 28 mmol), Pd(OAc)2 (313.6 mg, 1.4 mmol), tricyclohexylphosphene (784 mg, 2.8 mmol) and K3PO4 (5.9 g, 28 mmol) in dioxane/H20 (20 mL/20 mL) was stirred in a sealed tube at 100 C under N2 for 16 h. The reaction was concentrated to give the crude, which was purified by silica gel chromatography (PE/EA = 5/1) to give the 6-chloro-5-cyclopropylpyridin-2-amine (2.4 g, yield:
98%) as a white solid. ESI-MS [M+H]+ 169.2.
[0200] Synthesis of 5-chloro-2-(chloromethyl)-6-cyclopropylimidazo11,2-al pyridine.
A mixture of 6-chloro-5-cyclopropylpyridin-2-amine (2.4 g, 14.2 mmol) and 1,3-dichloropropan-2-one (7.16 g, 56.8 mmol) in ethanol (30 mL) was stirred at 78 C for 16 h.
The mixture was quenched with saturated NaHCO3 (50 mL) and extracted with DCM (100 mL x 3).
The combined organic layers were concentrated and purified by flash column silica gel chromatography (DCM/Me0H = 15/1) to give the 5-chloro-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1.8 g, yield: 53%) as a yellow solid. ESI-MS [M+H]+: 241.1.
[0201] Synthesis of ethyl 14(5-chloro-6-cyclopropylimidazo[1,2-alpyridin-yl)methyl)-1H-pyrazole-4-carboxylate. To a solution of 5-chloro-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (800 mg, 3.33 mmol) in dry DMF (10 mL) was added ethyl 1H-pyrazole-4-carboxylate (512.4 mg, 3.66 mmol) and Cs2CO3 (3.25 g, 10 mmol).Then the reaction mixture was stirred at 55 C for 16 h under N2 atmosphere. The mixture was cooled to RT, diluted with H20 (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (DCM/Me0H = 10/1) to give the ethyl 1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (870 mg, yield: 76%) as a white solid.
ESI-MS [M+H]+:
345.2.
[0202] Synthesis of 1-((5-chloro-6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl 145-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (300 mg,0.87 mmol) in THF (5 mL) and H20 (5 mL) was added Li0E11120 (110 mg, 2.62 mmol) , then the reaction mixture was stirred at 50 C for 16 h. The solvent was removed, and the pH of the residue was adjusted to around 5 by adding 1 M HC1 solution allowing a yellow solid was precipitate out. The mixture was filtered and the solid was dried to give the 14(5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (175 mg, yield: 64%) as a white solid. ESI-MS
[M+H]+: 317.1.
[0203] Synthesis of 1-((5-chloro-6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-N-((7-chloroimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1-23).
To a solution of 1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.32 mmol) in dry DNIF (3 mL) was added (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (69.4 mg, 0.32 mmol), HATU (182 mg,0.48 mmol) and DIPEA (124 mg, 0.96 mmol), the reaction mixture was stirred at RT for 16 h. The reaction mixture diluted with H20 (20 mL), extracted with ethyl acetate (30 mL x 3).
The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by prep-TLC (DCM/Me0H = 10/1) to afford 1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (15 mg, yield: 9.8%) as a white solid.
ESI-MS
[M+H]+: 480.1. Purity: 90.37%. 111 NMR (400 MHz, DMSO-d6): 6 8.58 (t, J = 5.5 Hz, 1H), 8.30 (d, J = 6.8 Hz, 2H), 8.24 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.50 (d, J = 9.3 Hz, 1H), 6.98 (d, J = 9.3 Hz, 1H), 6.64 (d, J = 7.5, 1.9 Hz, 1H), 5.46 (d, J = 9.6 Hz, 2H), 4.55 (d, J = 5.6 Hz,2H), 2.19-2.06 (m, 1H), 1.03 (m, 2H), 0.78 (m, 2H).

Example 24 Scheme 24 (21,11,(21 HIVAYIL
3aBr 1::>¨B(OH)2 CI
/ CI CI N CI Cs2CO3. MAL 60 C. 3 h H2N CI Pd(OAc), PCy3. K31304 DIVIt 100 C. 2 h ON
choxane/H20, 80 C. 6 h HaN

CI

LIOH. 1HF. Ethanol. H20 Oj, N NH
60 C. 3 h HO HAM. DIPEA. DIVIt
[0204] Synthesis of 4-chloro-5-cyclopropylpyridin-2-amine. A mixture of 5-bromo-4-chloropyridin-2-amine (3.24 g, 15.6 mmol), cyclopropylboronic acid (2.01 g, 23.4 mmol), Pd(OAc)2 (350 mg, 1.56 mmol), K3PO4 (6.62 g, 31.2 mmol) and PCy3 (875 mg, 3.12 mmol) in toluene (40 mL) and H20 (5 mL) was stirred at 80 C overnight. Water (100 mL) was added and the mixture was extracted with Et0Ac (100 mL x 3). The combined organics were concentrated and purified by silica gel chromatography (EA/PE = 2:3 to 10:1) to give 4-chloro-5-cyclopropylpyridin-2-amine (1.89 g, yield: 18.7%) as a yellow solid. ESI-MS
[M+H]: 169.1.
[0205] Synthesis of 7-chloro-2-(chloromethyl)-6-cyclopropylimidazo11,2-al pyridine.
To a solution of 4-chloro-5-cyclopropylpyridin-2-amine (1.2 g, 7.1 mmol) in DMF (20 mL) was added 1,3-dichloropropan-2-one (1.8 g, 14.2 mmol) at RT. After the mixture was stirred at 100 C for 2 h, H20 (50 mL) was added and extracted with Et0Ac (100 mL x 3). The combined organic layers were concentrated and purified by silica gel chromatography (EA/PE = 1:10 to 3:7) to give 7-chloro-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (674 mg, yield:
38%) as a yellow solid. ESI-MS [M+H]: 241.1.
[0206] Synthesis of ethyl 14(7-chloro-6-cyclopropylimidazo[1,2-alpyridin-yl)methyl)-1H-pyrazole-4-carboxylate. A mixture of 7-chloro-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (480 mg, 2.0 mmol), ethyl 1H-pyrazole-4-carboxylate (689 mg, 4.92 mmol) and Cs2CO3 (2.4 g, 7.38 mmol) in DMF (10 mL) was stirred at 60 C for 3 h.
Water (50 mL) was added and the mixture was extracted with Et0Ac (50 mL x 3).
The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude, which was purified by silica gel chromatography (EA/PE =
7:3 to 10:1) to ethyl 1((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (390 mg, yield: 57%) as a whilte solid. ESI-MS [M+H]: 345.1.
[0207] Synthesis of 1-((7-chloro-6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl 147-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (200 mg, 0.58 mmol) in ethanol/THF/H20 (3 mL/3 mL/1.5 mL) was added Li0H1120 (97 mg, 2.32 mmol). The reaction mixture was stirred at 65 C for 3 h. The mixture was then concentrated and then diluted with H20 (20 mL). The pH
of the aqueous layer was adjust to 4 by adding 1 M HC1 solution and extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated to give crude 1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (230 mg) as a white solid, which was used in the next step without further purification. ESI-MS [M+H]:
317.1.
[0208] Synthesis of 1-((7-chloro-6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-N-((7-chloroimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1-24).
A mixture of crude 1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (230 mg, 0.73 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (65.1 mg, 0.3 mmol), HATU (278 mg, 0.73 mmol) and DIPEA (375 mg, 2.9 mmol) in DMF (5 mL) was stirred at RT for 3 h. Water (30 mL) was added and the mixture was extracted with Et0Ac (50 mL x 3).The combined organic layers were concentrated and purified by prep-TLC
(DCM:Me0H = 8:1) to give 14(7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (11.1 mg, yield:
7.7%) as a white solid. ESI-MS [M+H]: 480Ø Purity: 98.15%. lEINIVIR (400 MHz, DMS0): 6 8.58 (t, J= 5.3 Hz, 1H), 8.40 (s, 1H), 8.31-8.30 (m, 2H), 8.20 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 6.65 (dd, J = 7.4, 1.8 Hz, 1H), 5.40 (s, 2H), 4.55 (d, J = 5.6 Hz, 2H), 1.98-1.94 (m, 1H), 0.95-0.94 (m, 2H), 0.66-0.65 (m, 2H).

Example 25 Scheme 25 (T:e etjaA CI
Br / N OCIN N

NH
HO HATU, DIPEA, DMF
Br / N 1-25 N-Synthesis of N-((7-bromoimidazo[1,5-alpyridin-1-yl)methyl)-1-((7-chloro-6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-25). A
mixture of crude 1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (230 mg, 0.73 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine (67.8 mg, 0.3 mmol), HATU (278 mg, 0.73 mmol) and DIPEA (375 mg, 2.9 mmol) in DMF (5 mL) was stirred at RT for 3 h. Water (30 mL) was added and the mixture was extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated and purified by prep-TLC
(DCM:Me0H = 8:1) to give N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (31.5 mg, yield:
20%) as a white solid. ESI-MS [M+H]+: 524Ø Purity: 97%. 'FINN/IR (400 MHz, DMS0): 6 8.58-8.57 (m, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 8.23-8.20 (m, 2H), 7.94 (s, 1H), 7.85 (s, 1H), 7.69 (d, J = 13.8 Hz, 2H), 6.72-6.71 (m, 1H), 5.39 (s, 2H), 4.54 (s, 2H), 1.95-1.93 (m, 1H), 0.94-0.93 (m, 2H), 0.65-0.64 (m, 2H).
Example 26 Scheme 26 Br 0 H2NM.-.X-j 0 Br N
NO-AOH ___________________________________________________________________ 1\
/
HATU, DIPEA, DMF, rt, 2 h N") __ /1\1 NI

[0210] Synthesis of N-((7-bromoimidazo[1,5-alpyridin-1-yl)methyl)-1-((5,6-dimethylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-26).
To the solution of 1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (54 mg, 0.2 mmol) in dry DMF (3 mL) was added HATU (114 mg, 0.3 mmol), DIPEA
(129 mg, 1.0 mmol) and (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (52.4 mg, 0.2 mmol) at RT. The reaction was stirred at RT for 2 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-HPLC to give N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5,6-dimethylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (9.7 mg, yield: 10.2%). ESI-MS [M+H]:
478.1. Purity: 90.33%. 1H NMIR (400 MHz, DMS0): 6 8.58 (t, J = 5.6 Hz, 1H), 8.31 (s, 1H), 8.28-8.18 (m, 2H), 7.95 (s, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.33 (d, J = 9.1 Hz, 1H), 7.14 (d, J =
9.2 Hz, 1H), 6.76-6.67 (m, 1H), 5.40 (s, 2H), 4.54 (d, J = 5.7 Hz, 2H), 2.49 (s, 3H), 2.29 (s, 3H).
Example 27 Scheme 27 CIYCI Br f) 0 HN
Br N4y-k0Et Li0H4120 Br Nt4...yk0H
Br N NH, DME, 90 C. 2.5 h Cs2CO3. DME, rt, 2 h THF/EION/H20,N
80 C, 2 h CI

CI elm%

HATU, DIPEA. MAE, rt, 2 h N 1-27 [0211] Synthesis of 5-bromo-2-(chloromethyl)imidazo11,2-al pyridine. To a solution of 6-bromopyridin-2-amine (800 mg, 4.6 mmol) in N,N-dimethylformamine (5 mL) was added 1,3-dichloropropan-2-one (3.05 g, 24.0 mmol). The resulting mixture was stirred at 90 C for 2.5 h. The reaction mixture was diluted with H20 (50 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give 5-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine (600 mg, yield: 53%). ESI-MS [M+H]+:
245Ø
[0212] Synthesis of ethyl 1-((5-bromoimidazo11,2-alpyridin-2-y1)methyl)-pyrazole-4-carboxylate. To a solution of 5-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine (200 mg, 0.82 mmol) in N,N-dimethylformamine (3 mL) was added cesium carbonate (1.1 g, 3.28 mmol) and ethyl 1H-pyrazole-4-carboxylate (115 mg, 0.82 mmol). The resulting mixture was stirred at RT for 2 h then diluted with H20 (50 mL) and extracted with ethyl acetate (3 x 30 mL).
The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give ethyl 14(5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (236 mg, yield:
83%). ESI-MS [M+H]+: 349Ø
[0213] Synthesis of 1-((5-bromoimidazo 11,2-al pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl 145-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (236 mg, 0.68 mmol) in the mixture of THF/H20 (3 mL/3 mL) was added lithium hydroxide (82 mg, 3.4 mmol). The resulting mixture was stirred at 80 C for 2 h.
THF was evaporated and the pH of the H20 phase was adjusted to 5 by adding 1 M
HC1 solution.
The resulting solid precipitate was filtered to give 145-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (131 mg, Yield: 60%), which was used in the next step without further purification. ESI-MS [M+H]+: 321Ø
[0214] Synthesis of 1-((5-bromoimidazo[1,2-alpyridin-2-y1)methyl)-N-((7-chloroimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1-27). To the solution of 1-((5-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (65 mg, 0.20 mmol) in dry DIVIF (3 mL) was added HATU (116 mg, 0.305 mmol), DIPEA
(131 mg, 1.02 mmol) and (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (44 mg, 0.20 mmol) at RT. The reaction was stirred at RT for 2 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-HPLC to give 1-((5-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (41 mg, yield: 37%). ESI-MS
[M+H]+:
484Ø Purity: 100%. 111 NMR (400 MHz, DMS0): 6 8.60 (t, J = 5.6 Hz, 1H), 8.39 (s, 1H), 8.32 (d, J = 7.5 Hz, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.31-7.21 (m, J = 8.7, 7.4 Hz, 1H), 6.72-6.63 (m, 1H), 5.48 (s, 2H), 4.57 (d, J = 5.7 Hz, 2H).
Example 28 Scheme 28 Cl )1142_ 0 NI H ). -CA
NH CI
Br N Br /CI 0 DMF Br Cs2CO3, DMF H

[0215] Synthesis of 6-bromo-2-(chloromethyl)-7-methylimidazo11,2-alpyridine. To a solution of 5-bromo-4-methylpyridin-2-amine (1000 mg, 5.37 mmol) in DMF (15 mL) was added 1,3-dichloropropan-2-one (2.04 g, 16.1 mmol) at RT. The resulting reaction was stirred at 85 C for 2 h. The solution was quenched with H20 (40 mL) and the pH of the mixture was adjusted to 8 by adding saturated a NaHCO3 solution. The resulting mixture was then extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with a silica gel column (PE/Et0Ac = 1/1) to give the 6-bromo-2-(chloromethyl)-7-methylimidazo[1,2-a]pyridine (500 mg, yield:36%) as a light yellow oil. ESI-MS [M+H]+: 259.2.
[0216] Synthesis of 1-((6-bromo-7-methylimidazo[1,2-alpyridin-2-y1)methyl)-N-((7-chloroimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1-28). To a solution 6-bromo-2-(chloromethyl)-7-methylimidazo[1,2-a]pyridine (56 mg, 0.22 mmol) in DMF (3 mL) was added N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole -4-carboxamide (40 mg, 0.14 mmol) and Cs2CO3 (140 mg, 0.43 mmol) at RT. The resulting reaction was stirred at RT for 12 h. H20 (30 mL) was added to the reaction and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with prep-TLC (DCM/Me0H = 10/1) to give the 1-((6-bromo-7-methylimidazo [1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (22 mg, yield: 32%) as a white solid. ESI-MS [M+H]+:

498Ø Purity: 98.7%. 111 NMR (400 MHz, DMS0): 6 8.89 (s, 1H), 8.60-8.57 (m, 1H), 8.31-8.29 (m, 2H), 8.22 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 6.65 (d, J = 7.4 Hz, 1H), 5.40 (s, 2H), 4.55 (d, J = 5.6 Hz, 2H), 2.36 (s, 3H).
Example 29 Scheme 29 H2N l\r-41Syl /
OH HATU, DIPEA, DMF Cs2CO3, DMF 1-29 NH N

[0217] Synthesis of N-((7-chloroimidazo 11,5-alpyridin-1-yl)methyl)-1H-pyrrolo 13,2-blpyridine-3-carboxamide. A mixture of 1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.62 mmol), 7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (160 mg, 0.74 mmol), HATU (290 mg, 0.78 mmol) and DIPEA (0.32 mL, 1.86 mmol) in DMF (5 mL) was stirred at RT for 16 h. Water (30 mL) was added and extracted with Et0Ac (30 mL x 3). The combined organic layers were concentrated and purified by prep-TLC (DCM/Me0H =
10/1) to give N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (60 mg, yield: 30%) as a yellow solid. ESI-MS [M+H]+: 326.1.
[0218] Synthesis of N-((7-chloroimidazo 11,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo [1,2-a] pyridin-2-yl)methyl)-1H-pyrrolo [3,2-b]pyridine-3-carboxamide (1-29). A mixture of N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (50 mg, 0.15 mmol), 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 mg, 0.19 mmol) and Cs2CO3 (125 mg, 0.39 mmol) in DNIF (5 mL) was stirred at RT
for 4 h.
Water (30 mL) was added and extracted with Et0Ac (30 mL x 3). The combined organic layers were concentrated and purified by prep-HPLC to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (9.1 mg, yield: 12%) as a yellow solid. ESI-MS [M+H]: 496.1.
Purity: 86.0%. 111 NMR (400 MHz, DMS0): 6 9.06 (t, J = 5.8 Hz, 1H), 8.43 (d, J = 4.7 Hz, 1H), 8.40-8.25 (m, 4H), 8.14 (d, J = 8.3 Hz, 1H), 7.87 (s, 1H), 7.73 (s, 1H), 7.37 (d, J = 9.4 Hz, 1H), 7.26 (dd, J = 8.3, 4.7 Hz, 1H), 6.97 (d, J = 9.4 Hz, 1H), 6.66 (dd, J = 7.4, 2.0 Hz, 1H), 5.59 (s, 2H), 4.77 (d, J = 5.7 Hz, 2H), 1.96-1.81 (m, 1H), 0.96-0.83 (m, 2H), 0.73-0.56 (m, 2H).
Example 30 Scheme 30 I
HATU, DIPEA, DMF NH 1-30 Cs2CO3, DMF / NH
OH

[0219] Synthesis of N-((7-bromoimidazo11,5-al pyridin-1-yl)methyl)-1H-pyrrolo [3,2-b] pyridine-3-carboxamide. A mixture of 1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.62 mmol), 7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (190 mg, 0.74 mmol), HATU (350 mg, 0.93 mmol) and DIPEA (0.32 mL, 1.86 mmol) in DMF (5 mL) was stirred at RT for 16 h. Water (30 mL) was added and the mixture was extracted with Et0Ac (30 mL x 3). The combined organic layers were concentrated and purified by prep-TLC
(DCM/Me0H = 10/1) to give N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (60 mg, yield: 20%) as a yellow solid. ESI-MS [M+H]+:
370.1.
[0220] Synthesis of N-((7-bromoimidazo11,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo [1,2-a] pyridin-2-yl)methyl)-1H-pyrrolo [3,2-b]pyridine-3-carboxamide (I-30). A mixture of N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (60 mg, 0.16 mmol), 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 mg, 0.19 mmol) and Cs2CO3 (125 mg, 0.39 mmol) in DNIF (5 mL) was stirred at RT
for 4 h.
Water (30 mL) was added and the mixture was extracted with Et0Ac (30 mL x 3).
The combined organic layers were concentrated and purified by prep-HPLC to give N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (13.0 mg, yield: 15%) as a yellow solid. ESI-MS
[M+H]+: 540.1. Purity: 89.1%. 111 NMR (400 MHz, DMS0): 6 9.06 (t, J = 6.0 Hz, 1H), 8.43 (d, J = 3.7 Hz, 1H), 8.36 (d, J = 5.4 Hz, 2H), 8.31-8.22 (m, 2H), 8.14 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.73 (s, 1H), 7.37 (d, J = 9.2 Hz, 1H), 7.26 (dd, J = 8.3, 4.7 Hz, 1H), 6.97 (d, J = 9.5 Hz, 1H), 6.81-6.67 (m, 1H), 5.59 (s, 2H), 4.77 (d, J = 5.8 Hz, 2H), 1.89 (d, J =
5.1 Hz, 1H), 0.96-0.84 (m, 2H), 0.64 (d, J = 5.1 Hz, 2H).
Example 31 Scheme 31 0¨ N
0¨

pi]
DMF-DMA
N2H4 H20, AcOH HN, DME 110 C, 10 h Et0H, reIux. 12 h Cs,CO3, DIVIE
rt. 1 h 0 \ 0 \
Cl I Cl LØ
Me0H, I HP. H20, 70 C, 1 h HATU, DIVIE DIPEA, ty, 2h [0221] Synthesis of methyl 2-((dimethylamino)methylene)-4-methoxy-3-oxobutanoate. A mixture of methyl 4-methoxy-3-oxobutanoate (500 mg, 3.42 mmol) and DMF-DMA (410 mg, 3.42 mmol) in dry DMF (5 mL) was stirred at 110 C for 10 h. The mixture was concentrated to give methyl 2-((dimethylamino)methylene)-4-methoxy-3-oxobutanoate (600 mg, yield: 87%) as a yellow oil. ESI-MS [M+H]+: 202.1.
102221 Synthesis of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate. A
solution of methyl 2-((dimethylamino)methylene)-4-methoxy-3-oxobutanoate (600 mg, 3.0 mmol), N2H44-120 (0.15 mL, 3.0 mmol) and AcOH (0.21 mL, 3.6 mmol) in dry Et0H
(10 mL) was stirred at reflux for 12 h. The mixture was concentrated and purified by prep-TLC
(DCM/Me0H = 30/1) to give methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (400 mg, yield: 78%) as a brown solid. ESI-MS [M+H]+: 171.1.
[0223] Synthesis of methyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylate and methyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxylate. A mixture of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (100 mg, 0.59 mmol), 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (150 mg, 0.70 mmol) and Cs2CO3 (480 mg, 1.48 mmol) in DMF (5 mL) was stirred at RT for 16 h. Water (50 mL) was added and the mixture was extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated and purified by prep-TLC (DCM/Me0H = 15/1) to give methyl 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylate (100 mg, yield: 50.0%) as a light yellow solid.
ESI-MS [M+H]: 341.1 and methyl 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxylate (50 mg, yield: 25.0%) as a light yellow solid. ESI-MS [M+H]: 341.1.
[0224] Synthesis of 1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylic acid. A solution of methyl 14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylate (100 mg, 0.29 mmol) and Li0H.H20 (40 mg, 0.88 mmol) in THF/Me0H/H20 (2 mL/2 mL/1 mL) was stirred at 70 C for 1 h. Solvent was evaporated and the pH value of the residue was adjusted to 5 by adding 1 M HC1 solution. The resulting solid precipitate was filtered to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylic acid (90 mg, yield: 94.7%) as a yellow oil which was used in the next step without purification. ESI-MS [M+H]: 327.1.
[0225] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo11,2-a]pyridin-2-y1)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide (I-31). A mixture of 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylic acid (45 mg, 0.14 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (36 mg, 0.17 mmol), HATU (105 mg, 0.28 mmol) and DIPEA (0.1 mL, 0.41 mmol) in DNIF (3 mL) was stirred at RT for 2 h. Water (30 mL) was added and the mixture was extracted with Et0Ac (30 mL x 3). The combined organic layers were concentrated and purified by prep-TLC (DCM/Me0H = 10/1) to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-pyrazole-4-carboxamide (19.6 mg, yield: 29%) as a white solid. ESI-MS [M+H]:
490.1. Purity:
97.6%. 1-H NMR (400 MHz, DMS0): 6 8.49 (s, 1H), 8.41-8.28 (m, 3H), 8.23 (s, 1H), 7.90 (s, 1H), 7.79 (s, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.29 (s, 1H), 6.66 (d, J = 6.3 Hz, 1H), 5.46 (s, 2H), 4.57 (d, J = 5.2 Hz, 2H), 4.53 (s, 2H), 3.20 (s, 3H), 1.99 (s, 1H), 0.97 (d, J
= 7.5 Hz, 2H), 0.71 (d, J = 5.4 Hz, 2H).

Example 32 Scheme 32 CI
\ LAOH vCNrijTh\ilr I
I i?
Me0H, UHF, H20, 70 C. I h 4 \ HATU, DMF DIPEA. rt72 h [0226] Synthesis of 1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxylic acid. A solution of methyl 14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxylate (50 mg, 0.15 mmol) and Li0H.H20 (20 mg, 0.44 mmol) in THF/Me0H/H20 (2 mL/2 mL/1 mL) was stirred at 70 C for 1 h. Solvent was evaporated and the pH of the residue was adjusted to 5 by adding 1 M HC1 solution. Solid precipitated and was filtered to give 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxylic acid (45 mg, yield: 94.7%) as a yellow oil. ESI-MS [M+H]+: 327.1.
[0227] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo11,2-a]pyridin-2-y1)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxamide (1-32). A mixture of 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylic acid (45 mg, 0.14 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (36 mg, 0.17 mmol), HATU (105 mg, 0.28 mmol) and DIPEA (0.1 mL, 0.41 mmol) in DMF (5 mL) was stirred at RT for 2 h. Water (30 mL) was added and the mixture was extracted with Et0Ac (30 mL x 3). The combined organic layers were concentrated and purified by prep-TLC (DCM/Me0H = 10/1) to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxymethyl)-pyrazole-4-carboxamide (40.0 mg, yield: 59%) as a white solid. ESI-MS [M+H]+:
490.1. Purity:
99.2%. 111NMR (400 MHz, DMS0): 6 8.67 (s, 1H), 8.58 (s, 1H), 8.44-8.27 (m, 2H), 8.02 (s, 1H), 7.94 (s, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 6.67 (d, J = 7.2 Hz, 1H), 5.58 (s, 2H), 4.95 (s, 2H), 4.60 (d, J = 5.5 Hz, 2H), 3.25 (s, 3H), 2.05 (d, J = 16.1 Hz, 1H), 1.04 (t, J = 18.0 Hz, 2H), 0.74 (s, 2H).

Example 33 Scheme 33 0=C=N, ,CF13 CI\ /0 Si-CF13 CI CI CI CI CI CI HCOOH
POC13, DMF LiA1H4, THF
N n-BuLi, Me4-piperidine, Et20 N NH 2 N
N

ii 1) H2NrS Ti(0E04 CI CI CI
___s........ICI CI CI CI CI 0 _),..
\ / I00 C, 3 h N ----o------/
2) NaBH4, THF
----.._--r---N-N H

HO)LCN
N N,.....-.1/
\ .....,/i Clo.......r....C1 0 I
HC1 in dioxane CI C
\ , 0----.7...-CNH2 N H
HATU, DIPEA, DMF, \_.-:-=N N
N...-.--zN 25 C,1 h \ __ V

[0228] Synthesis of 3,4-dichloropicolinamide. To a solution of 2,2,6,6-tetramethylpiperidine (5.2 g, 37.2 mmol) in diethyl ether (80 mL) at 0 C was added n-BuLi (2.4 M, 15.5 mL, 37.2 mmol) dropwise. The resulting solution was stirred at 0 C
for 0.5 h and at -78 C for 0.5 h. To this mixture was then slowly added a solution of 3,4-dichloropyridine (5 g, 33.8 mmol) in diethyl ether (10 mL) dropwise. The resulting mixture was stirred at -78 C for 2 h before the addition of isocyanotrimethylsilane (5.83 g, 50.7 mmol). After the addition, the cooling bath was removed and the reaction mixture was allowed to warm to RT
over 1 h. The reaction mixture was stirred at 25 C for 16 h, H20 (100 mL) was added, extracted with ethyl acetate (100 mL x 3), washed with brine (30 mL), dried over MgSO4 and concentrated in vacuo.
The residue was suspended in 20 mL of diethyl ether and sonicated. The solid was collected through filtration and washed with minimum amount of diethyl ether to give 3,4-dichloropicolinamide (2.3 g, yield: 35%) as a yellow solid. ESI-MS [M+H]+:
191.1.
[0229] Synthesis of 3,4-dichloropicolinonitrile. To a solution of 3,4-dichloropicolinamide (500 mg, 2.63 mmol) in DMF (20 mL) was added POC13 (2.4 g, 15.79 mmol) dropwise at 0 C. The mixture was stirred at 25 C for 16 h, then saturated NaHCO3 (aq., 120 mL) was added and the reaction mixture was extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated to give 3,4-dichloropicolinonitrile (420 mg, yield: 93%) as a brown solid. ESI-MS
[M+H]: 173Ø
[0230] Synthesis of (3,4-dichloropyridin-2-yl)methanamine. To a mixture of LiA1H4 (110 mg, 2.9 mmol) in dry THF (3 mL) was added 3,4-dichloropicolinonitrile (200 mg, 1.16 mmol) in THF at -78 C. The mixture was stirred at -78 C for 30 min, then stirred at -40 C for 30 min. The mixture was quenched with H20 (10 mL), extracted with Et0Ac (50 mL
x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated to give (3,4-dichloropyridin-2-yl)methanamine (100 mg, yield: 49%) as a yellow oil. ESI-MS
[M+H]:
177Ø
[0231] Synthesis of N-((3,4-dichloropyridin-2-yl)methyl)formamide. The mixture of (3,4-dichloropyridin-2-yl)methanamine (100 mg, 0.57 mmol) in HCOOH (2 mL) was stirred at 90 C for 3 h and then concentrated to give the crude. The crude was purified by prep-TLC
(DCM/Me0H = 10/1) to give N-((3,4-dichloropyridin-2-yl)methyl)formamide (70 mg, yield:
60%) as a yellow oil. ESI-MS [M+H]: 205.1.
[0232] Synthesis of 7,8-dichloroimidazo[1,5-a] pyridine. The mixture of N-((3,4-dichloropyridin-2-yl)methyl)formamide (70 mg, 0.34 mmol) in POC13 (2 mL) was stirred at 100 C for 3 h. Then POC13 was concentrated, H20 (10 mL) was added, followed by saturated Na2CO3 (20 mL). The mixture was extracted with Et0Ac (50 mL*3) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude, which was purified by prep-TLC (PE/EA = 1/2) to give 7,8-dichloroimidazo[1,5-a]pyridine (40 mg, yield: 63%) as a yellow solid. ESI-MS [M+H]: 187Ø
[0233] Synthesis of 7,8-dichloroimidazo11,5-alpyridine-1-carbaldehyde. To a solution of 7,8-dichloroimidazo[1,5-a]pyridine (100 mg, 0.54 mmol) in dry DIVIF (0.2 mL) was added POC13 (123 mg, 0.81 mmol) at 0 C. The mixture was stirred at 100 C for 1 h then cooled and poured into ice H20. The mixture was basified with NH4OH, extracted with DCM
(50 mL x 3) and concentrated to give the crude, which was purified by prep-TLC (DCM/Me0H =
20/1) to give 7,8-dichloroimidazo[1,5-a]pyridine-1-carbaldehyde (25 mg, yield: 22%) as a yellow solid.
ESI-MS [M+H]: 215Ø

[0234] Synthesis of N-((7,8-dichloroimidazo11,5-alpyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide. To a mixture of 7,8-dichloroimidazo[1,5-a]pyridine-1-carbaldehyde (25 mg, 0.12 mmol) and 2-methylpropane-2-sulfinamide (17 mg, 0.14 mmol) in dry THF (2 mL) was added tetraethoxytitanium (80 mg, 0.35 mmol). The mixture was stirred at 75 C for 16 h and then cooled to 25 C. NaBH4 (18 mg, 0.47 mmol) was added and stirred at 25 C for 3 h. The reaction was quenched with H20 (10 mL) and extracted with Et0Ac (30 mL x 3).
The combined organic layers were washed with brine, dried over Na2SO4, concentrated to give N47,8-dichloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (37 mg, yield: 100%) as a yellow solid. ESI-MS [M+H]: 320Ø
[0235] Synthesis of (7,8-dichloroimidazo[1,5-alpyridin-1-yl)methanamine.
The mixture of N47,8-dichloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (37 mg, 0.12 mmol) and HC1 in dioxane (1 mL, 4 M) was stirred at 25 C for 3 h. The resulting mixture was concentrated to give (7,8-dichloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (25 mg, yield: 84%) as a yellow solid which was used in the next step without purification. ESI-MS [M-16]: 199Ø
[0236] Synthesis of N-((7,8-dichloroimidazo[1,5-alpyridin-1-y1)methyl)-1-((6-methylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-33). To a mixture of (7,8-dichloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (25 mg, 0.1 mmol) and 1((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (25 mg, 0.1 mmol) in dry DMF (2 mL) was added DIPEA (64 mg, 0.5 mmol) and HATU (76 mg, 0.2 mmol).
The mixture was stirred at 25 C for 1 h. Water (20 mL) was added and extracted with Et0Ac (30 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated to give the crude, which was purified by prep-TLC (DCM/Me0H =
10/1) to give N47,8-dichloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (13.3 mg, yield: 30%) as a yellow solid.
ESI-MS
[M+H]: 454.1. Purity: 96.7%. 111 NMR (400 MHz, DMS0): 6 8.44 (s, 1H), 8.35 (d, J = 7.4 Hz, 1H), 8.32-8.27 (m, 2H), 8.22 (s, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.41 (d, J =
9.2 Hz, 1H), 7.11 (d, J = 9.2 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 5.39 (s, 2H), 4.80 (d, J = 4.9 Hz, 2H), 2.25 (s, 3H).

Example 34 Scheme 34 CI /

NCS
,41) CI
NH, DME. -10 C, 2 h N H2 DME. 90 C, 2 5 h Cs2C.03, DME. rt, 2 h N NL'OEtN
CI

H2NTh----(3 IT01-1.1-120 H20/Et0H/THF. - HATU, DIPEA, DME. rt, 3 h CI N ;NI H
80 C. 1 5 h 1-34 [0237] Synthesis of 5-chloro-6-ethylpyridin-2-amine. To a solution of 6-ethylpyridin-2-amine (1.0 g, 8.20 mmol) in dry DMF (16 mL) was added NCS (1.09 g, 8.2 mmol) at -10 C
and stirred at -10 C for 2 h. The reaction mixture was diluted with H20 (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give 5-chloro-6-ethylpyridin-2-amine (500 mg, yield: 39%). ESI-MS [M+H]+:
157.1.
[0238] Synthesis of 6-chloro-2-(chloromethyl)-5-ethylimidazo11,2-al pyridine. To a solution of 5-chloro-6-ethylpyridin-2-amine (500 mg, 3.2 mmol) in N,N-dimethylformamine (3 mL) was added 1,3-dichloropropan-2-one (1.62 g, 12.8 mmol). The resulting mixture was stirred at 90 C for 2.5 h. The reaction mixture was diluted with H20 (50 mL), adjust to approximately pH 9 by adding saturated NaHCO3 solution, and then extracted with ethyl acetate (3 x 30 mL).
The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give 6-chloro-2-(chloromethyl)-5-ethylimidazo[1,2-a]pyridine (390 mg, yield: 37%). ESI-MS
[M+H]+: 229.1.
[0239] Synthesis of ethyl 14(6-chloro-5-ethylimidazo[1,2-alpyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. To a solution of 6-chloro-2-(chloromethyl)-5-ethylimidazo[1,2-a]pyridine (250 mg, 1.11 mmol) in N,N-dimethylformamine (3 mL) was added cesium carbonate (1.80 g, 3.33 mmol) and ethyl 1H-pyrazole-4-carboxylate (155 mg , 1.11 mmol).
The resulting mixture was diluted with H20 (30 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give ethyl 1-((6-chloro-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (360 mg, yield: 87%). ESI-MS [M+H]+: 333.1.
[0240] Synthesis of 1-((6-chloro-5-ethylimidazo11,2-alpyridin-2-y1)methyl)-111-pyrazole-4-carboxylic acid. To a solution of give ethyl 146-chloro-5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (436 mg, 1.3 mmol) in a mixed solvent of THF/Et0H/H20 (3 mL/3 mL/1 mL) was added lithium hydroxide (126 mg, 5.3 mmol).
The resulting mixture was stirred at 85 C for 1.5 h and diluted with H20 (15 mL).
The pH of the mixture was then adjusted to 5 by adding 1 M HC1 and then extracted with DCM/Me0H (5/1, 3 x 50 mL). The combined organic layers were concentrated to give 146-chloro-5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (200 mg, yield: 50%), which was used in the next step without further purification. ESI-MS [M+H]:
305.1.
[0241] Synthesis of 1-((6-chloro-5-ethylimidazo[1,2-alpyridin-2-y1)methyl)-N-((7-chloroimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1-34). To the solution of 1-((6-chloro-5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (65 mg, 0.21 mmol) in dry DIVIF (3 mL) was added HATU (120 mg, 0.32 mmol), DIPEA
(135 mg, 1.05 mmol) and (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (46 mg, 0.21 mmol) at RT. The reaction was stirred at RT for 2 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-HPLC to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-145-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (41 mg, yield: 38%) as a white solid. ESI-MS [M+H]: 468Ø Purity: 100%. 1H NMR (400 MHz, DMS0): 6 8.59 (t, J = 5.7 Hz, 1H), 8.34-8.26 (m, 2H), 8.24 (s, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.46 (d, J = 9.5 Hz, 1H), 7.34 (d, J = 9.5 Hz, 1H), 6.69-6.60 (m, 1H), 5.43 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 3.20-3.10 (m, 2H), 1.20 (t, J = 7.5 Hz, 3H).

Example 35 Scheme 35 ci c]
DCM, 4 h TMSCN, TE,A BH3 in THF, 0 HCOOH
\ NI DMF, 4 h H2N 80 C, 2 h H
NC
TL

H2N' POCI, CI POCI3, DMF H Ti(oEt)4, THF, 80 C ci \S.* HCI
in dioxane CI

110 C, 2 h 100 C, 1 h 2) NaBH4 Me0H, 1.5 h HO)VN

N)L-0=1 H
HATU, DIPEA, DMF, 50 C, 1.5 h [0242] Synthesis of 4-chloro-3-methylpyridine 1-oxide. To a solution of 4-chloro-3-methylpyridine (5 g, 30.6 mmol) in dry DNIF (100 mL) was added m-CPBA (10.8 g, 58.9 mmol). The reaction was stirred at RT for 3 h. The mixture was diluted with DCM (300 mL) and followed by saturated NaHCO3 (300 mL). Then the mixture was extracted with DCM
(300 mL x 3). The combined organic layers were concentrated and purified by silica gel chromatography (DCM/Me0H = 15/1) to give 4-chloro-3-methylpyridine 1-oxide (2.43 g, yield:
55.4%) as a white solid. ESI-MS [M+H]+: 144.2.
[0243] Synthesis of 4-chloro-3-methylpicolinonitrile. To a solution of 4-chloro-3-methylpyridine 1-oxide (2.43 g, 17.0 mmol), dimethylcarbamic chloride (1.92 g, 17.9 mmol) and TMSCN (2.02 g, 20.4 mmol) in dry DMF (45 mL) was added Et3N (4.7 mL, 34 mmol), the mixture was stirred at 100 C for 3 h. The reaction mixture was then quenched with saturated NaHCO3 (200 mL) solution at 0 C and extracted with Et0Ac (100 mL x 3). The combined organic layers were concentrated and purified by silica gel chromatography (EA/PE = 1/10) to give 4-chloro-3-methylpicolinonitrile (1.87 g, yield: 72%) as a yellow oil.
ESI-MS [M+H]:
153.1.
[0244] Synthesis of (4-chloro-3-methylpyridin-2-yl)methanamine. To a solution of 4-chloro-3-methylpicolinonitrile (1.7 g, 11 mmol) in dry THF (6 mL) was added BH3-THF (1 M, 27.5 mL) at 0 C. The mixture was stirred at 0 C for 1 h and then stirred at RT overnight. The mixture was quenched with Me0H and stirred at RT for 1 h, then concentrated to give (4-chloro-3-methylpyridin-2-yl)methanamine (2.1 g, crude) as a yellow solid which was used in the next step without purification. ESI-MS [M+H]+: 185.1.
[0245] Synthesis of N-((4-chloro-3-methylpyridin-2-yl)methyl)formamide.
To a solution of 4-chloro-3-methylpicolinonitrile (2.1 g, 13.5 mmol) and formic acid (20 mL) was stirred at 80 C for 3 h. The mixture was concentrated and purified by silica gel chromatography to give N-((4-chloro-3-methylpyridin-2-yl)methyl)formamide (1.3 g, yield: 54%) as a brown oil.
ESI-MS [M+H]: 185.1.
[0246] Synthesis of 7-chloro-8-methylimidazo[1,5-a] pyridine. To a solution of N-((4-chloro-3-methylpyridin-2-yl)methyl)formamide (1.3 g, 7 mmol) and POC13 (22 mL) was stirred at 110 C for 2 h. POC13was removed in vacuo. Water was added and followed by saturated Na2CO3(aq.). The mixture was extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude, which was purified by silica gel chromatography (EA/PE = 1/1) to give 7-chloro-methylimidazo[1,5-a]pyridine (700 mg, yield: 60%) as a brown solid. ESI-MS
[M+H]: 167.1.
[0247] Synthesis of 7-chloro-8-methylimidazo11,5-alpyridine-1-carbaldehyde. A
mixture of 7-chloro-8-methylimidazo[1,5-a]pyridine (660 mg, 3.96 mmol), DIVIF
(289.4 mg, 3.96 mmol) in POC13 (5 mL) was stirred at 100 C for 1 h. Then the reaction mixture was poured to ice H20. NH4OH solution was added to adjust pH to about 8 and then the mixture was extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated and purified by silica gel chromatography to give 7-chloro-8-methylimidazo[1,5-a]pyridine-1-carbaldehyde (165 mg, yield: 21%) as a white solid. ESI-MS [M+H]: 195.1.
[0248] Synthesis of N-((7-chloro-8-methylimidazo11,5-alpyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide. A mixture of 7-chloro-8-methylimidazo[1,5-a]pyridine-1-carbaldehyde (154 mg, 0.8 mmol), 2-methylpropane-2-sulfinamide (116.35 mg, 0.96 mmol) and Ti(0E04 (0.58 mL, 2.8 mmol) in THF (10 mL) was stirred at 80 C overnight.
After cooled to RT, NaBH4 (151.32 mg, 4 mmol) was added. The reaction mixture was stirred at RT for 3 h. The reaction was quenched with H20 (20 mL) and extracted with Et0Ac (50 mL x 3).
The combined organic layers were concentrated and purified by silica gel chromatography (DCM/CH3OH =

10:1) to give N-((7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (87 mg, yield: 36%) as a yellow solid. ESI-MS [M+H]+: 300, and (131 mg, yield:
36%) as a yellow solid. ESI-MS [M+13]+: 312.
[0249] Synthesis of (7-chloro-8-methylimidazo11,5-alpyridin-1-yl)methanamine. To a solution of N-((7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (187 mg, 0.62 mmol) in CH3OH (8 mL) was added HC1 (4 M in dioxane, 8 mL).
The mixture was stirred at RT for 1.5 h. Then concentrated to give (7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methanamine hydorchloride (168 mg, crude) as a white solid which was used in the next step without purifiation. ESI-MS [M-16]+: 179.1.
[0250] Synthesis of N-((7-chloro-8-methylimidazo[1,5-alpyridin-1-y1)methyl)-1-((6-methylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-35). A
mixture (7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methanamine (44 mg, 0.22 mmol), 14(6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (57 mg, 0.22 mmol), HATU (167.2 mg, 0.44 mmol) and DIPEA (113.5 mg, 0.88 mmol) in DMF (5 mL) was stirred at RT for 1.5 h. Water (30 mL) was added, extracted with Et0Ac (30 mL x 3), the combined organic phase were washed with brine, dried over Na2SO4 and concentrated to give the crude, which was purified by silica gel chromatography (DCM/Me0H = 10:1) to give N-((7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (27 mg, yield: 28%) as a white solid. ESI-MS [M+H]+:
434.1. Purity:
99.42%. 1-H NMR (400 MHz, DMS0): 6 8.33 (t, J = 4.7 Hz, 1H), 8.26 (s, 2H), 8.17 (s, 1H), 8.13 (d, J = 7.3 Hz, 1H), 7.81 (s, 1H), 7.72 (s, 1H), 7.36 (d, J = 9.2 Hz, 1H), 7.08 (d, J = 9.2 Hz, 1H), 6.59 (d, J = 7.4 Hz, 1H), 5.33 (s, 2H), 4.62 (d, J = 4.9 Hz, 2H), 2.51 (s, 3H), 2.19 (s, 3H).

Example 36 Scheme 36 Br 1) Br CI
LiOH THE ethanol H 0 C C 01; N 'N
H2N - CI DMF, 90 C, 5 h Cs2CHON;N, --DMF, 60 C, 3 h 60 C, 3 h CI
aõ Br B
CI r HATU, DIPEA, DMF, rt, 3 h HO CI (11-[0251] Synthesis of 6-bromo-7-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine. A
mixture of 5-bromo-4-chloropyridin-2-amine (1.67 g, 9.9 mmol), 1,3-dichloropropan-2-one (2.5 g, 19.8 mmol) in DMF (15 mL) was stirred at 90 C for 5 h. The reaction mixture was diluted with H20 (50 mL), adjusted to approximately pH 9 by adding saturated a NaHCO3 solution, and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were concentrated and purified by silica gel chromatography (EA/PE = 7:1) to give 6-bromo-7-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (900 mg, yield: 32%) as a yellow solid.
ESI-MS [M+H]:
278.9.
[0252] Synthesis of ethyl 1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. A mixture of 6-bromo-7-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (560 mg, 2.0 mmol), ethyl 1H-pyrazole-4-carboxylate (560 mg, 4.0 mmol) and Cs2CO3 (1.95 g, 6.0 mmol) in DMF (10 mL) was stirred at 60 C for 3 h. The resulting mixture was diluted with H20 (30 mL) and extracted with ethyl acetate (3 x 30 mL), The combined organic layers were concentrated and purified by silica gel chromatography (EA/PE = 10:1 to 7:13) to give ethyl 1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (400 mg, yield: 52%) as a white solid. ESI-MS [M+H]: 383Ø
[0253] Synthesis of 1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-111-pyrazole-4-carboxylic acid. To a solution of ethyl 14(6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (216 mg, 0.56 mmol) in ethanol (3 mL), THF (3 mL) and H20 (1.5 mL) was added Li0H1120 (95 mg, 2.25 mmol). The mixture was stirred at 65 C
for 3 h. Most of the solvent was concentrated and theresidue was adjusted to pH to 4 by adding 1 M HC1 solution. The resulting precipitate was filtered to give 14(6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (190 mg, yield: 95%) as a white solid.
ESI-MS [M+H]: 355Ø
[0254] Synthesis of 1-((6-bromo-7-chloroimidazo[1,2-alpyridin-2-y1)methyl)-N-((7-chloroimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1-36). A
mixture of 1((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (95 mg, 0.27 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (55 mg, 0.25 mmol), HATU (190 mg, 0.5 mmol) and DIPEA (97 mg, 0.75 mmol) in DMF (4 mL) was stirred at RT for 3 h. Water (30 mL) was added and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were concentrated and purified by prep-TLC (DCM:Me0H = 8:1) to give 1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (49.2 mg, yield: 38%) as a white solid. ESI-MS [M+H]:
517.9. Purity:
96.34%. 111NMR (400 MHz, DMS0): 6 9.06 (s, 1H), 8.58 (s, 1H), 8.30-8.22 (m, 3H), 7.92-7.77 (m, 4H), 6.64 (s, 1H), 5.42 (s, 2H), 4.54 (s, 2H).
Example 37 Scheme 37 B
__________ N Br r fssz-N
Br ir,C)\1 HATU, DIPEA, DMF, rt, 3 h HO Br 0 [0255] Synthesis of 1-((6-bromo-7-chloroimidazo[1,2-alpyridin-2-y1)methyl)-N-((7-bromoimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1-37). A
mixture of 1((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (95 mg, 0.27 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine (56 mg, 0.25 mmol), HATU (190 mg, 0.5 mmol) and DIPEA (97 mg, 0.75 mmol) in DMF (4 mL) was stirred at RT for 3 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were concentrated and purified by prep-TLC (DCM:Me0H = 8:1) to give 1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (43.3 mg, yield: 31%) as a white solid.
ESI-MS [M+H]+:
561.9. Purity: 90%. 1H NMR (400 MHz, DMS0): 6 9.06 (s, 1H), 8.58 (t, J = 4.9 Hz, 1H), 8.31 (s, 1H), 8.23-8.22 (m, 2H), 7.94-7.93 (m, 2H), 7.86 (s, 1H), 7.80 (s, 1H), 6.71 (d, J = 7.3 Hz, 1H), 5.43 (s, 2H), 4.54 (d, J = 5.3 Hz, 2H).
Example 38 Scheme 38 NEls 0 /¨ 0 0 0 ,¨(=> NET in Me0H N
Lawesson's reagent Et0H, 90 C, 15 h 60 C, sealed tube NTI
THE dioxane rt 6 h Li0H, THF/Et0H/H20 OH
S S
- Pyridine, Et0H, 80 C, 2 h 65 C, 14 h CI
__________ vCr--====, N N-5'\
HATU, DIPEA, DMF NN)(R
rt, 2 h 1-38 CI
[0256] Synthesis of ethyl 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate. A
mixture of 5-cyclopropylpyridin-2-amine (3 g, 22.4 mmol) and ethyl 4-chloro-3-oxobutanoate (11 g, 67.2 mmol) in Et0H (150 mL) was stirred at 90 C for 15 h. The pH of the reaction was adjusted to 8-9 with NaHCO3 (4 M, 50 mL) and extracted with Et0Ac (70 mL x 3).
The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude, which was purified by silica gel chromatography (EA/PE = 1/1) to give ethyl 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate (3.6 g, yield: 72%) as a black solid. ESI-MS
[M+H]+: 225.2.

[0257] Synthesis of 2-(6-cyclopropylimidazo11,2-a] pyridin-2-yl)acetamide. A solution of ethyl 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate (3.6 g, 16 mmol) in NH3 (7 M
solution in Me0H, 50 mL) in sealed tube was stirred at 60 C for 12 h. The reaction was concentrated to give the 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetamide, which was used in the next step without further purification (3.4 g, yield: 99%) as a yellow oil. ESI-MS [M+H]:
216.2.
[0258] Synthesis of 2-(6-cyclopropylimidazo11,2-alpyridin-2-yl)ethanethioamide. To a solution of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetamide (3.4 g, 15.8 mmol) in dioxane (50 mL) was added Lawesson's reagent (6.3 g, 15.8 mmol) at 0 C. The resulting mixture was stirred at RT for 6 h. The reaction was quenched with H20 (70 mL) and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethanethioamide which was used in the next step without further purification. (3 g, yield:
82%) as a yellow oil. ESI-MS [M+H]: 232.2.
[0259] Synthesis of ethyl 2-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)thiazole-5-carboxylate. A mixture of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethanethioamide (700 mg, 3.1 mmol), pyridine (480 mg, 6.2 mmol) and ethyl 2-chloro-3-oxopropanoate (678 mg, 4.65 mmol) in Et0H (25 mL) was stirred at 65 C for 14 h. The reaction was concentrated to give the crude, which was purified with silica gel chromatography (EA/PE =
1/1) to give the ethyl 2((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)thiazole-5-carboxylate (105 mg, yield: 10.7%) as a yellow solid. ESI-MS [M+H]: 327.1.
[0260] Synthesis of 2-((6-cyclopropylimidazo 11,2-al pyridin-2-yl)methyl)thiazole-5-carboxylic acid. A mixture of ethyl 246-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)thiazole-5-carboxylate (105 mg, 0.32 mmol) and LiOH (23 mg, 0.96 mmol) in THF/Et0H/H20 (2 mL/2 mL/1 mL) was stirred at 80 C for 2 h. The pH value of the reaction was adjusted to 4 by adding 1 M HC1 solution, and then concentrated to give the crude, which was used in the next step without further purification (105 mg, crude yield:
100%). ESI-MS
[M+H]: 300.2.
[0261] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)thiazole-5-carboxamide (1-38). To a solution of 24(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)thiazole-5-carboxylic acid (105 mg, crude from last step) in DMF (5 mL) was added HATU (160 mg, 0.42 mmol) and DIPEA (226 mg, 1.75 mmol). The mixture reaction was stirred for 30 min, then (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (99 mg, 0.45 mmol) was added. The resulting mixture was stirred at RT for 12 h. Water (25 mL) was added and the mixture was extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated to give the crude, which was purified with prep-TLC (DCM/Me0H =
10/1) to give the N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-246-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)thiazole-5-carboxamide as a white solid (15 mg, yield: 9.3%). ESI-MS
[M+H]+: 463.1.
Purity: 98.5%. IENNIR (400 MHz, Me0D): 6 8.30-8.27 (m, 2H), 8.19-8.16 (m, 2H), 7.81 (s, 1H), 7.73 (s, 1H), 7.49 (d, J = 9.4 Hz, 1H), 7.30 (dd, J = 9.4, 1.5 Hz, 1H), 6.63 (dd, J = 7.5, 2.0 Hz, 1H), 4.70 (s, 2H), 4.53 (s, 2H), 1.99-1.97 (m, 1H), 1.11-1.00 (m, 2H), 0.77-0.74 (m, 2H).
Example 39 Scheme 39 ci CI CI N
N) Br CI
Br /
DMF, 95 C, 4 h Cs2CO3, DMF, N 0.
50 C, 4 h Br mi2 Br CI CI

LiOH=H20, THF). L \)--\
N N
N ___________________ )0-40 C,16 h \ OH HATU, DIPEA, DMF, rt, 1 h CI

[0262] Synthesis of 6-bromo-5-chloro-2-(chloromethyl)imidazo[1,2-a]
pyridine. The mixture of 5-bromo-6-chloropyridin-2-amine (1.38 g, 6.65 mmol) and 1,3-dichloropropan-2-one (3.35 g, 26.61 mmol) in DMF (20 mL) was stirred at 95 C for 4 h. The reaction mixture was quenched with H20 (150 mL) followed by adding saturated NaHCO3 (20 mL) solution, the mixture was then extracted with Et0Ac (100 mL x 2). The combined organic layers were washed with brine (150 mL x 2), dried over Na2SO4, concentrated and purified by trituration with Et0Ac to give 6-bromo-5-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (480 mg, 26%) as a light brown solid. ESI-MS [M+H]+: 279Ø
[0263] Synthesis of ethyl 1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. The mixture of 6-bromo-5-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (380 mg, 1.36 mmol), ethyl 1H-pyrazole-4-carboxylate (190 mg, 1.36 mmol) and CsCO3 (663 mg, 2.04 mmol) in DNIF (10 mL) was stirred for at 50 C for 4 h.
The reaction mixture was diluted with H20 (80 mL) and extracted with Et0Ac (100 mL x 3).
The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE = 1/4) to give ethyl 1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (400 mg, yield: 77%) as a yellow solid.
ESI-MS [M+H]+:
383Ø
[0264] Synthesis of 1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-111-pyrazole-4-carboxylic acid. A mixture of ethyl 1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (350 mg, 0.912 mmol) and Li0H+120 (307 mg, 7.30 mmol) in THF (10 mL) and H20 (2 mL) was stirred at 40 C for 16 h. Most of the solvent was removed and the residue was diluted with H20 (10 mL). The pH value of mixture was adjusted to 4-5 by adding HC1 (1 M). The precipitate was collected and dried to give 146-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (285 mg, yield: 88%) as a white solid. ESI-MS [M+H]+: 354.9.
[0265] Synthesis of 1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (1-39). The mixture of 1((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (80 mg, 0.22 mmol), HATU (92 mg, 0.242 mmol) and DIPEA (85 mg, 0.66 mmol) in DMF
(3 mL) was stirred at RT for 10 min. (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (48 mg, 0.22 mmol) was added and stirred at RT for 1 h. The reaction mixture was quenched with H20 (50 mL) and extracted with Et0Ac/THF (40 mL x 3, 5/1 (v/v)). The combined organic layers was washed with brine (100 mL x 3), dried over Na2SO4, concentrated and purified by prep-TLC (DCM/Me0H = 7/1) to give 146-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (50 mg, yield: 43%) as a yellow solid. ESI-MS [M+H]: 518Ø Purity: 99.23%. 1H NIVIR
(400 MHz, DMS0): 6 8.59 (t, J = 5.7 Hz, 1H), 8.33-8.28 (m, 2H), 8.25 (s, 1H), 8.02 (s, 1H), 7.87 (s, 1H), 7.78-7.77 (m, 1H), 7.62-7.55 (m, 2H), 6.66-6.63 (m, 1H), 5.47 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H).
Example 40 Scheme 40 NH, CI Br_____C CI
Br N HCI Br, I\l"-) I\I \
10,1õcf-N \ \ OH HATU, DIPEA, DMF, rt, 1 h Br [0266] Synthesis of 1-((6-bromo-5-chloroimidazo[1,2-alpyridin-2-y1)methyl)-N-((7-bromoimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (I-40). The mixture of 1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (70 mg, 0.20 mmol), HATU (82 mg, 0.217 mmol) and DIPEA (76 mg, 0.591 mmol) in DMF
(3 mL) was stirred at RT for 10 min. (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (52 mg, 0.20 mmol) was added and stirred at RT for 1 h. The reaction mixture was diluted with H20 (50 mL) and extracted with Et0Ac/THF (40 mL x 3, 5/1 (v/v)). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, concentrated and purified by prep-TLC (DCM/Me0H = 7/1) to give 146-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (40 mg, yield: 36%) as a yellow solid. ESI-MS [M+H]: 561.9. Purity: 92.54%. 1H NIVIR
(400 MHz, DMS0): 6 8.58 (t, J = 5.5 Hz, 1H), 8.32 (s, 1H), 8.26-8.22 (m, 2H), 8.02 (s, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.61-7.55 (m, 2H), 6.72 (d, J = 8.9 Hz, 1H), 5.47 (s, 2H), 4.55 (d, J = 5.6 Hz, 2H).

Example 41 Scheme 41 13,0\17-12>__\N
is0/
N LAOH. THF/Me0H
Pd(Ac0)2, PCy6. K3PO4 IV.s.,..)0 H20, 80 C, 2 h 1V3,OH
0 microwave. 1O00 CI
HATU, DIPEA 1..,(1)\
MAE rt, 2 h 1-41 CI
[0267] Synthesis of ethyl 1-07-(2,2-dimethylcyclopropyl)imidazo11,2-a]pyridin-2-yHmethyl)-1H-pyrazole-4-carboxylate. A mixture of ethyl 1-((7-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (120 mg, 0.34 mmol), 2-(2,2-dimethylcyclopropy1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (0.33 g, 1.7 mmol), Pd(OAc)2 (8 mg, 0.034), PCy3 (10 mg, 0.034 mmol), and K3PO4(220 mg, 1.3 mmol) in 1,4-dioxane (3 mL) and H20 (1 mL) was stirred at 100 C under microwave for 7 h. The reaction was filtered through celite and washed with DCM/Me0H (10/1, 30 mL). The filtrate was concentrated and purified by silica gel (DCM/Me0H = 10/1) to give the 14(7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (60 mg, 70%) as a yellow solid. ESI-MS
[M+H]+: 339.1.
[0268] Synthesis of ethyl 1-07-(2,2-dimethylcyclopropyl)imidazo11,2-a]pyridin-2-yHmethyl)-1H-pyrazole-4-carboxylate. A mixture of 14(742,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (61 mg, 0.18 mmol) and LiOH (27.6 mg, 1.2 mmol) in THF/Et0H/H20 (3 mL/3 mL/2 mL) was stirred at 80 C for 2 h. The pH value of the reaction was adjusted to around 5 and a yellow solid precipitated out. The solid was filtered and the filter cake was dried to give 14(742,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (50 mg, yield: 89%) as a yellow solid. ESI-MS [M+H]: 311.1.
[0269] Synthesis of N-((7-chloroimidazo11,5-a]pyridin-1-yl)methyl)-1-47-(2,2-dimethylcyclopropyl)imidazo11,2-a]pyridin-2-yHmethyl)-1H-pyrazole-4-carboxamide (I-41). To a solution of 14(7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (55 mg, 0.18 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (38 mg, 0.21 mmol) and HATU (101 mg, 0.27 mmol) in DMF (15 mL) was added DIPEA
(187 mg, 1.55 mmol). The resulting reaction stirred at RT for 2 h. H20 (30 mL) was added to the reaction and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with prep-TLC (DCM/Me0H = 10/1) to give the N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-147-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (12.3 mg, yield: 10%) as a white solid. ESI-MS [M+H]+: 474.1. Purity: 94.0%. 1H
NIVIR (400 MHz, Me0D): 6 8.27 (d, J = 2.7 Hz, 2H), 8.20-8.15 (m, 2H), 7.93 (s, 1H), 7.85 (s, 1H), 7.74 (m, 1H), 7.52-7.47 (m, 2H), 6.68-6.60 (m, 1H), 5.52 (s, 2H), 4.69 (s, 2H), 1.95-1.88 (m, 1H), 1.26 (s, 3H), 0.89 (s, 1H), 0.88 (d, J = 2.5 Hz, 1H), 0.83 (s, 3H).
[0270] Synthesis of 2-(2,2-dimethylcyclopropy1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. To a solution of 4,4,5,5-tetramethy1-2-(2-methylprop-1-en-l-y1)-1,3,2-dioxaborolane (100 mg, 0.55 mmol) in toluene (5 mL) was added CH2I2 (0.42 g, 1.54 mmol) dropwise at 0 C. The resulting reaction was stirred at 55 C overnight. The reaction was filtered and washed with DCM (10 mL). The crude product was extracted with H20 (10 mL), dried over Na2SO4, concentrated to give the 2-(2,2-dimethylcyclopropy1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (200 mg crude) which was used in the next step without further purification. ESI-MS [M+H]+: 197.1.
Example 42 Scheme 42 XI
N ( LION, THF/Me0I-I), N
Pd(dript)Cl2.1(3PO4 10...1c,0 H20, 80 C. 2 h 1\rOH
microwave, I00 C

N.:AN

CI N
HATU, DIPEA 1-42 DME. rt, 2 h CI

[0271] Synthesis of ethyl 1-07-(2-methylprop-1-en-1-yl)imidazo11,2-a]pyridin-2-yHmethyl)-1H-pyrazole-4-carboxylate. A solution of ethyl 14(7-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (200 mg, 0.57 mmol), 4,4,5,5-tetramethy1-2-(2-methylprop-1-en-l-y1)-1,3,2-dioxaborolane (207 mg, 1.14 mmol), Pd(dppf)C12 (42, 0.057 mg), and K3PO4 (364 mg, 1.72 mmol) in 1,4-dioxane (10 mL) and H20 (1 mL) in a sealed tube was stirred at 100 C under microwave for 3 h. The reaction was filtered through celite and washed with Et0Ac. The filtrate was concentrated and purified by silica gel (PE/EA =
1:2) to give the 1-((7-(2-methylprop-1 -en-l-yl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate (200 mg, 90%) as a brown solid. ESI-MS [M+H]+: 325.1.
[0272] Synthesis of 1-47-(2-methylprop-1-en-1-yl)imidazo11,2-a]pyridin-2-yHmethyl)-1H-pyrazole-4-carboxylic acid. A mixture of 1-((7-(2-methylprop-1-en-l-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate (60 mg, 0.18 mmol) and LiOH (27 mg, 1.2 mmol) in THF/Et0H/H20 (3 mL/3 mL/2 mL) was stirred at 80 C
for 2 h. The pH value of reaction was adjusted to around 5 by adding 1 M HC1 solution and a solid was precipitated. The solid was filtered and the filter cake was dried to give 1-((7-(2-methylprop-1-en-l-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid (50 mg, yield: 89%) as a brown solid. ESI-MS [M+H]+: 297.1.
[0273] Synthesis of N-((7-chloroimidazo11,5-a]pyridin-1-yl)methyl)-1-47-(2-methylprop-1-en-1-yl)imidazo11,2-a]pyridin-2-yHmethyl)-1H-pyrazole-4-carboxamide (I-42). To a solution of 1-((7-(2-methylprop-1-en-l-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid (53 mg, 0.18 mmol), (7-chloroimidazo[1,5-a]pyridin-yl)methanamine (38 mg, 0.21 mmol) and HATU (101 mg, 0.27 mmol) in DIVIF (15 mL) was added DIPEA (200 mg, 1.55 mmol). The resulting reaction stirred at RT for 2 h.
H20 (30 mL) was added and the reaction mixture was extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified by prep-TLC (DCM/Me0H = 10/1) to give the N4(7-chloroimidazo[1,5-a]pyridin-l-y1)methyl)-147-(2-methylprop-1-en-1-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (30 mg, yield: 36%) as a white solid.
ESI-MS [M+H]:
460.1. Purity: 95.2%. 11-1NMR (400 MHz, Me0D): 6 8.35 (s, 1H), 8.28 (s, 1H), 8.18-8.46 (m, 2H), 7.94 (s, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.54 (d, J = 9.3 Hz, 1H), 7.49-7.38 (m, 1H), 6.63 (dd, J = 7.5, 1.9 Hz, 1H), 6.22 (s, 1H), 5.54 (s, 2H), 4.69 (s, 2H), 1.95 (s, 3H), 1.88 (s, 3H).

Example 43 Scheme 43 ;00), Br IrGN
Pd(dppf)C12, KOAc TFA CH1.Lrht Cij*"..C1 0 HBoc 100 C. 16 h , 22 2 N Br 1\1' HBoc DCM, 0 C to rt. N
H2DMF.9OC.2h 0 NI-- Cs2CO3, DMh Pd(PP63)4, Cs2CO3 rt, 2 h I00 C, 16 h 0 NH, CkciXN,,,. 0 Et0\1 Na0H, Et0H HON
reflux, 3 h 1\1-- HATO, DIEA, DMh --rt, h 1-43 1\1 [0274] Synthesis of tert-butyl (Z)-(5-(prop-1-en-l-y1)pyridin-2-y1)carbamate. To a mixture of tert-butyl (5-bromopyridin-2-yl)carbamate (2.73 g, 10 mmol), 4,4,4',4',5,5,5',5'-octamethy1-2,2'-bi(1,3,2-dioxaborolane) (3.81 g, 15 mmol) and KOAc (3.0 g, 30 mmol) in dioxane (30 mL) was added Pd(dppf)C12 (881 mg, 1 mmol). The mixture was stirred at 100 C
for 16 h. After cooling, (Z)-1-bromoprop-1-ene (3.6 g, 30 mmol), Cs2CO3 (6.4 g, 20 mmol) and Pd(PPh3)4 (500 mg, 0.5 mmol) were added. The mixture was stirred 100 C for another 16 h.
Water (100 mL) was added and the mixture was extracted with Et0Ac (100 mL x 3). The combined organic layers were concentrated and purified by silica gel chromatography (EA/PE =
1/2) to give tert-butyl (Z)-(5-(prop-1-en-1-yl)pyridin-2-yl)carbamate (230 mg, yield: 10%) as a white solid. ESI-MS [M+H]+: 235.1.
[0275] Synthesis of 5-(2-methylcyclopropyl)pyridin-2-amine. To a solution of ZflEt2 (1 M, lOmmL) in DCM (20 mL) was added TFA (1.14 g, 10 mmol), followed by CH2I2 (2.68 g, mmol). After the resulting mixture was stirred at 0 C for 10 min, tert-butyl (Z)-(5-(prop-1-en-1-yl)pyridin-2-yl)carbamate (230 mg, 1.0 mmol) was added. The mixture was stirred at RT
for 3 h. Water (50 mL) was added and extracted with Et0Ac (100 mL x 3). The combined organic layers were concentrated and purified by prep-HPLC to give 5-(2-methylcyclopropyl)pyridin-2-amine (60 mg, yield: 12%) as a yellow oil. ESI-MS
[M+H]:
149.1.

[0276] Synthesis of 2-(chloromethyl)-6-(2-methylcyclopropyl)imidazo 11,2-alpyridine. To a solution of 5-(2-methylcyclopropyl)pyridin-2-amine (600 mg, 0.4 mmol) in DMF (5 mL) was added 1,3-dichloropropan-2-one (206 mg, 1.6 mmol). The mixture was stirred at 90 C for 2 h. Water (50 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude, which was purified by silica gel chromatography (EA/PE =
1/1) to give 2-(chloromethyl)-6-(2-methylcyclopropyl)imidazo[1,2-a]pyridine (40 mg, yield:
79%) as a yellow oil. ESI-MS [M+H]+: 221.1.
[0277] Synthesis of ethyl 1-06-(2-methylcyclopropyl)imidazo11,2-alpyridin-y1)methyl)-1H-pyrazole-4-carboxylate. To a solution of 2-(chloromethyl)-6-(2-methylcyclopropyl)imidazo[1,2-a]pyridine (40 mg, 0.18 mmol) and ethyl 1H-pyrazole-4-carboxylate (30 mg, 0.22 mmol) in DMF (3 mL) was added CsCO3 (118 mg, 0.36 mmol) at RT.
The mixture was stirred at RT for 2 h. The reaction was diluted with H20 (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated and purified by prep-TLC(Me0H/DCM = 1/10) to give ethyl 1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (30 mg, yield: 50%) as a yellow oil. ESI-MS [M+H]+: 325.1.
[0278] Synthesis of 1-46-(2-methylcyclopropyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl 1-((64(1S,2R)-2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (30 mg, 0.1 mmol) in a mixed solvent of THF/Et0H/H20 (2 mL/2 mL/1 mL) was added NaOH (4 M, 0.1 mL, 0.4 mmol). The mixture was stirred at refluxed for 3 h. Most of the solvent was removed and the residue was diluted with H20 (3 mL) and the pH value of mixture was adjusted to 4-5 by adding HC1 aqueous (1 M). The mixture was freeze-dried to give 14(642-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (crude, 40 mg) as a yellow solid which was used in the next step without purification.
ESI-MS [M+H]:
297.1.
[0279] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-46-(2-methylcyclopropyl)imidazo11,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (1-43).
To a solution of 1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (40 mg, crude from last step) and (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (44 mg, 0.2 mmol) in dry DMF (1 mL) was added HATU (106 mg, 0.28 mmol) and DIPEA (90 mg, 0.7 mmol) at RT. The reaction was stirred at RT for 3 h.
Water (20 mL) was added and the mixture was extracted with Et0Ac (30 mL x 3).
The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, concentrated and purified by prep-TLC (DCM/Me0H = 10/1) to give N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-3-carboxamide (25 mg, yield: 54% for two steps) as a yellow solid. ESI-MS
[M+H]+: 460.1.
Purity: 91%. 111 NMR (400 MHz, DMS0): 6 8.58 (t, J = 5.3 Hz, 1H), 8.31-8.29 (m, 3H), 8.23 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.73 (s, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.14 (d, J = 8.9 Hz, 1H), 6.64 (dd, J = 7.5, 1.9 Hz, 1H), 5.39 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 2.02 (dd, J = 14.3, 8.6 Hz, 1H), 1.18-1.07 (m, 1H), 1.04-0.88 (m, 1H), 0.75 (d, J = 6.2 Hz, 3H), 0.60 (dd, J = 10.5, 5.2 Hz, 1H).
Example 44 Scheme 44 0 Br Br HO)LON NH
_______________________________________ -= = 0 HATU, DIEA, DMF
-N
rt, 3 h [0280] Synthesis of N-((7-bromoimidazo[1,5-alpyridin-1-yl)methyl)-1-06-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yOmethyl)-1H-pyrazole-4-carboxamide (1-44).
To a solution of 1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (40 mg, 0.1 mmol) and (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (52 mg, 0.2 mmol) in dry DMF (3 mL) was added HATU (106 mg, 0.28 mmol) and DIPEA (90 mg, 0.7 mmol) at RT. The reaction was stirred at RT for 3 h.
Water (20 mL) was added and the mixture was extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, concentrated and purified by prep-TLC (DCM/Me0H = 10/1) to give N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (25.5 mg, yield: 37%) as a yellow solid. ESI-MS [M+H]: 504.1. Purity: 91.53%. 1H NIVIR
(400 MHz, DMS0): 6 8.59 (t, J = 5.7 Hz, 1H), 8.31 (s, 2H), 8.26-8.19 (m, 2H), 8.00-7.92 (m, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.15 (dd, J = 9.3, 1.6 Hz, 1H), 6.72 (dd, J = 7.4, 1.9 Hz, 1H), 5.39 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 2.02 (dd, J = 14.4, 8.4 Hz, 1H), 1.18-1.11 (m, 1H), 0.99-0.93 (m, 1H), 0.75 (d, J = 6.2 Hz, 3H), 0.60 (dd, J = 10.7, 5.5 Hz, 1H).
Example 45 Scheme 45 N?
0H H2N I I \I 31 t\ir 431c HATU, DIEA, DMF

[0281] Synthesis of 1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-N-((7-iodoimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1-45). To a solution of 1((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (60 mg, 0.21 mmol), (7-iodoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (99 mg, 0.32 mmol) and HATU (120 mg, 0.31 mmol) in DIVIF (5 mL) was added DIPEA (81 mg, 0.63 mmol). The resulting reaction was stirred at RT for 12 h. H20 (25 mL) was added to the reaction, extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with prep-TLC
(DCM/Me0H = 10/1) to give the 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-iodoimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (20 mg, yield: 18%) as a white solid. ESI-MS [M+H]: 538Ø Purity: 97.4%. 111 NMR (400 MHz, DMS0): 6 8.56 (t, J =
5.7 Hz, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 8.12-8.08 (m, 1H), 7.85 (s, 1H), 7.71 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 6.99 (dd, J = 9.3, 1.7 Hz, 1H), 6.78 (dd, J = 7.3, 1.6 Hz, 1H), 5.39 (s, 2H), 4.54 (d, J = 5.7 Hz, 2H), 1.94-1.88 (m, 1H), 0.96-0.85 (m, 2H), 0.71-0.58 (m, 2H).

Example 46 Scheme 46 N
HN

C1)=CI CI
N
al0 N \N
H2N DMF, 90 C, 2 h Cs2CO3, DMF, 2 h Cl [0282] Synthesis of 2-(chloromethyl)-5-ethylimidazo 11,2-al pyridine. A
solution of 6-ethylpyridin-2-amine (1 g, 8.2 mmol) and 1, 3-dichloropropan-2-one (4.7 g, 36.9 mmol) in DMF
(10 mL) was stirred at 90 C for 3 h. Then the reaction mixture was diluted with H20 (100 mL) and extracted with Et0Ac (100 mL x 3). The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography (CH2C12: Me0H = 20:1) to give the desired product 2-(chloromethyl)-5-ethylimidazo[1,2-a]pyridine (450 mg, yield:
28%) as a white solid. ESI-MS [M+H]+: 195.1.
[0283] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((5-ethylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-46). A
solution of 2-(chloromethyl)-5-ethylimidazo[1,2-a]pyridine (60 mg, 0.31 mmol), N-((7-chloroimidazo[1,5-a]pyridin-l-yl)methyl)-1H-pyrazole-4-carboxamide and Cs2CO3 (303 mg, 0.93 mmol) in DMF
(3 mL) was stirred at RT for 2 h. Then the reaction mixture was diluted with H20 (50 mL) and extracted with Et0Ac (50 mL x 3). The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography (CH2C12/Me0H = 20/1) to give the desired compound N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-145-ethylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (16 mg, yield: 12%) as a white solid. ESI-MS [M+H]+:
434.1. Purity: 98.90%. 111 NMR (400 MHz, DMS0): 6 8.58 (t, J= 5.8 Hz, 2H), 8.33-8.27 (m, 2H), 8.23 (s, 1H), 7.86 (d, J = 6.8 Hz, 2H), 7.80-7.75 (m, 1H), 7.42 (d, J =
9.0 Hz, 1H), 7.29-7.21 (m, 1H), 6.78-6.73 (m, 1H), 6.67-6.61 (m, 1H), 5.42 (s, 2H), 4.55 (d, J = 5.8 Hz, 2H), 2.95-2.86 m, 2H), 1.36-1.27 (m, 3H).

Example 47 Scheme 47 _N NaOH NH2 N
N
Th _______________________________________________ Et0H/1420 HATU DIEA, DME NH

[0284] Synthesis of (Z)-1-06-(prop-1-en-1-yl)imidazo[1,2-alpyridin-2-y1)methyl)-111-pyrazole-4-carboxylic acid. A mixture of ethyl (Z)-146-(prop-1-en-l-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (150 mg, 0.48 mmol) and NaOH
(40 mg, 1.6 mmol) in Et0H/H20 (2 mL/1 mL) was stirred at 50 C for 3 h. The reaction was monitored by LCMS until the starting material consumed. The pH value of mixture was adjusted to 2-3 by adding 1 M aqueous HC1 solution and extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated to give (Z)-146-(prop-1-en-l-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid (65 mg, 48% yield) as a white solid. ESI-MS
[M+H]: 283Ø
[0285] Synthesis of (Z)-N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-46-(prop-1-en-1-yl)imidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-47).
A mixture of 1((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (65 mg, 0.23 mmol) in DMF (3 mL) was added (5-chloro-2H-indazol-3-yl)methanamine hydrochloride (100 mg, 0.46 mmol), DIPEA (150 mg, 1.15 mmol) and HATU (133 mg, 0.35 mmol). The resulting mixture was stirred at RT for 3 h. The reaction was quenched with H20 (30 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with prep-TLC (EA/PE =
1/5) to give the (Z)-N-((7-chloroimidazo[1,5-a]pyridin-l-yl)methyl)-146-(prop-1-en-l-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (9.3 mg, yield: 6.2%) as a white solid. ESI-MS [M+H]: 446.1. Purity: 95.3%. 1H NMR (400 MHz, DMS0): 6 8.60 (t, J =
5.6 Hz, 1H), 8.50 (s, 1H), 8.38-8.26 (m, 2H), 8.24 (s, 1H), 7.87 (s, 1H), 7.80 (d, J = 14.2 Hz, 2H), 7.48 (d, J = 9.3 Hz, 1H), 7.22 (d, J = 9.3 Hz, 1H), 6.65 (dd, J = 7.4, 2.0 Hz, 1H), 6.35 (d, J =
11.5 Hz, 1H), 5.84 (td, J= 14.4, 7.1 Hz, 1H), 5.42 (s, 2H), 4.56 (d, J = 5.7 Hz, 2H), 1.87 (dd, J =
7.2, 1.6 Hz, 3H).

Example 48 Scheme 48 1j¨B(OH)2 nfaioõ, Pd(OAc)2, SPhos, K3PO4 NH, Cs2CO3, Toluene/H20 NH, , LAOH N¨N.)¨Al H
14310H ___________________________ I HP, I-10 HATU, DIEA, DMF

[0286] Synthesis of 5-cyclopropylpyridin-2-amine. A solution of 5-bromopyridin-2-amine (5 g, 29.1 mmol), cyclopropylboronic acid (3.75 g, 43.6 mmol), Pd(OAc)2 (651 mg, 2.91 mmol), SPhos (1.19 g, 2.91 mmol) and K3PO4 (18.5 g, 87.3 mmol) in toluene/H20 (100 mL/10 mL) was stirred at 95 C for 12 h under nitrogen. Then the reaction mixture was quenched with H20 (50 mL) and extracted with DCM (200 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the crude residue which was purified by silica gel chromatography (PE/Et0Ac = 1/1) to give the 5-cyclopropylpyridin-2-amine as yellow solid (3.8 g, 97.4% yield). ESI-MS [M+H]+: 135.2.
[0287] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo11,2-al pyridine.
To a solution 5-cyclopropy1-4-methylpyridin-2-amine (500 mg, 3.70 mmol) in DMF (10 mL) was added 1,3-dichloropropan-2-one (1409 mg, 11.1 mmol) at RT. The resulting reaction was stirred at 85 C for 2 h. The solution was quenched with H20 (60 mL),adjusted to pH 8 by adding saturated NaHCO3 solution, and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude, which was purified with prep-TLC (PE/Et0Ac = 1/1) to give the 2-(chloromethyl)-cyclopropy1-7-methylimidazo[1,2-a]pyridine (300 mg, yield:39%) as a light yellow oil. ESI-MS
[M+H]+: 207.2.
[0288] Synthesis of ethyl 14(6-cyclopropylimidazo[1,2-alpyridin-2-yl)methyl)-111-pyrazole-4-carboxylate. To a solution 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (2 g, 9.70 mmol) in DMF (20 mL) was added ethyl 1H-pyrazole-4-carboxylate (906 mg, 6.46 mmol) and Cs2CO3(6.32 g, 19.38 mmol) at RT. The resulting reaction was stirred at RT for 12 h.
H20 (150 mL) was added to the reaction and then the mixture was extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/Me0H =
20/1) to give the ethyl 14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.5 g, yield: 75%) as a white solid. ESI-MS [M+H]+: 311.2.
[0289] Synthesis of 1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-pyrazole-4-carboxylic acid. To a solution of ethyl 14(6-cyclopropylimidazo[1,2-a]pyridin-2-y1) methyl)-1H-pyrazole-4-carboxylate (1.2 g, 3.87 mmol) in THF (20 mL) and H20 (10 mL) was added LiOH (464 mg, 19.35 mmol). The mixture was stirred at RT for 16 h. Most of the THF
was removed and the pH was adjusted to 4-5 by adding HC1 (1 M). The resulting precipitate was collected and dried to give the 1-((6-cyclopropylimidazo [1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid as a white solid (1.0 g, yield: 91%). ESI-MS
[M+H]+: 283.2.
[0290] Synthesis of 1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-N-((7-cyclopropylimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1-48). To a solution of 1((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (60 mg, 0.21 mmol), (7-cyclopropylimidazo[1,5-a]pyridin-1-yl)methanamine (59 mg, 0.32 mmol) and HATU (120 mg, 0.31 mmol) in DMF (5 mL) was added DIPEA (81 mg, 0.63 mmol).
The resulting reaction was stirred at RT for 12 h. H2O (30 mL) was added to the reaction, extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with prep-TLC
(DCM/Me0H = 10/1) to give the 1-((6-cyclopropylimidazo [1,2-a]pyridin-2-yl)methyl)-N-((7-cyclopropylimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (20 mg, yield: 21%) as a white solid. ESI-MS [M+H]+: 452.2. Purity: 99.8%. 11-1NWIR (400 MHz, DMS0): 6 8.47 (t, J = 5.6 Hz, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 8.16-8.14 (m, 2H), 7.86 (s, 1H), 7.71 (s, 1H), 7.40-7.38 (m, 1H), 7.32 (s, 1H), 7.00-6.97 (m, 1H), 6.32-6.30 (m, 1H), 5.38 (s, 2H), 4.55 (d, J = 5.6 Hz, 2H), 1.95-1.78 (m, 2H), 0.95-0.83 (m, 4H), 0.70-0.60 (m, 4H).

Example 49 Scheme 49 )A\CrN
Br \ N N";\
43,1(1\11 I\13õ,r OH HATU, DIPEA
DMF, rt, 2 h 0 Br [0291] Synthesis of N-((7-bromoimidazo11,5-alpyridin-1-yl)methyl)-1-07-(2,2-dimethylcyclopropyl)imidazo11,2-alpyridin-2-yHmethyl)-1H-pyrazole-4-carboxamide (I-49). To a solution of 14(7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (56 mg, 0.18 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (55 mg, 0.21 mmol) and HATU (102 mg, 0.27 mmol) in DMF (10 mL) was added DIPEA (199 mg, 1.55 mmol). The resulting reaction stirred at RT for 2 h. H20 (30 mL) was added to the reaction and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with prep-TLC (DCM/Me0H = 10/1) to give the N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (17.5 mg, yield: 18.8%) as a white solid. ESI-MS [M+H]+: 518.1.
Purity: 91.25%.
1H NIVIR (400 MHz, Me0D): 6 8.85 (s, 1H), 8.53 (s, 1H), 8.30 (s, 1H), 8.24 (d, J = 7.5 Hz, 1H), 8.11 (s, 2H), 7.98 (s, 1H), 7.87 (dd, J = 9.3, 1.4 Hz, 1H), 7.75 (d, J = 9.3 Hz, 1H), 6.98 (dd, J =
7.5, 1.4 Hz, 1H), 5.68 (s, 2H), 4.77 (s, 2H), 2.03-1.98 (m, 1H), 1.29 (s, 3H), 1.00-0.93 (m, 2H), 0.85 (s, 3H).

Example 50 Scheme 50 =II-0, ____________________________________________ e õB 0 HO I 2 N OH
0 O¨

I 0 H2S0, Pd(dppB2C1, K2CO, DCM, 20.0 ND
0 0 NFI2 DBU, CH3CN H20. dt N=oxane Bt Doxane/H20 0 S'0 H
HN
OH C I 3-.1N
CI
OCl2 S 0 LIAIH4 N'N2 50.0 ¨ Cs2C0F, DMF, 50.0 CI
[0292] Synthesis of 4-cyclopropylpyridine. A mixture of 4-bromopyridine (5 g, 25.71 mmol), cyclopropylboronic acid (2.5 g, 28.28 mmol), K2CO3 (10.6 g, 77.13 mmol) and Pd(dppf)2C12 (2.1 g, 2.57 mmol) in dioxane (80 mL) and H20 (16 mL) was refluxed under N2 for 16 h. The reaction mixture was filtered through celite and washed with Et0Ac (20 mL). The solvent was evaporated, the residue was diluted with H20 (30 mL) and extracted with Et0Ac (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a yellow oil, which was purified by silica gel chromatography to give 4-cyclopropylpyridine (2.774 g, yield: 91.5%) as a yellow oil. ESI-MS [M+H]+: 120.1.
[0293] Synthesis of 1-amino-4-cyclopropylpyridin-1-ium 2,4,6-trimethylbenzenesulfonate. To a solution of 4-cyclopropylpyridine (1.5 g, 12.61 mmol) in DCM (5 mL) was added 0-(mesitylsulfonyl)hydroxylamine (2.7 g, 12.61 mmol) at 0 C, then the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated to give the 1-amino-4-cyclopropylpyridin-1-ium 2,4,6-trimethylbenzenesulfonate (4.2 g, yield: 100%) as a yellow oil, which was used in the next step without further purification. ESI-MS [M+H]: 135.1.
[0294] Synthesis of dimethyl 5-cyclopropylpyrazolo[1,5-a] pyridine-2,3-dicarboxylate. To a solution of 1-amino-4-cyclopropylpyridin-1-ium 2, 6-dimethylbenzenesulfonate (4.2 g, 12.6 mmol) and dimethyl but-2-ynedioate (3.6 g, 25.22 mmol) in CH3CN (60 mL) was added DBU (3.8 g, 25.22 mmol) at 0 C for 30 min. Then the resulting mixture was stirred at RT for 16 h. The reaction mixture was concentrated to give the crude, which was purified with silica gel chromatography (PE/EA = 2/1) to give dimethyl 5-cyclopropylpyrazolo[1,5-a]pyridine-2, 3-dicarboxylate (2.5 g, yield: 72.4%) as a yellow oil. ESI-MS [M+H]+: 275.1.
[0295] Synthesis of 5-cyclopropylpyrazolo11,5-alpyridine-2-carboxylic acid. A
mixture of dimethyl 5-cyclopropylpyrazolo [1, 5-a] pyridine-2, 3-dicarboxylate (1.5 g, 5.47 mmol) and 50% H2504 in dioxane (8 mL) was heated at 85 C for 5 h. Water (20 mL) was added and the mixture was extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to givethe crude, which was purified by silica gel chromatography (PE/EA = 1/1) to give 5-cyclopropylpyrazolo [1,5-a]
pyridine-2-carboxylic acid (600 mg, yield: 54.0%) as a white solid. ESI-MS
[M+H]+: 203.1.
[0296] Synthesis of (5-cyclopropylpyrazolo11,5-alpyridin-2-yl)methanol To a solution of 5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylic acid (202 mg, 1.0 mmol) in THF
(10 mL) was added LiAH4(1.5 mL, 1 M) at 0 C, the reaction mixture was stirred at 0 C for 30 min. then warmed to RT and stirred for 4 h. The reaction was quenched by H20 (10 mL) resulting in a precipitate. The filtrate was concentrated to give (5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methanol (140 mg, yield: 74.5%) as a yellow oil which was used in the next step without further purification. ESI-MS [M+H]+: 189.1.
[0297] Synthesis of 2-(chloromethyl)-5-cyclopropylpyrazolo11,5-al pyridine. A
mixture of (5-cyclopropylpyrazolo [1,5-a]pyridin-2-y1) methanol (140 mg, 0.74 mmol) and SOC12 (3 mL) was stirred at 50 C for 1 h. The reaction mixture was concentrated to give the crude product 2-(chloromethyl)-5-cyclopropylpyrazolo[1,5-a]pyridine (200 mg, crude) as a black oil which was used in the next step without purification. ESI-MS [M+H]+:
207.1.
[0298] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((5-cyclopropylpyrazolo[1,5-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-50). A
mixture of 2-(chloromethyl)-5-cyclopropylpyrazolo[1,5-a]pyridine (30 mg, 0.15 mmol), N-((7-chloroimidazo [1, 5-a] pyridin-1-y1) methyl)-1H-pyrazole-4-carboxamide (42 mg, 0.15 mmol), Cs2CO3 (200 mg, 0.61 mmol) in DIVIF (3 mL) was stirred at 50 C for 16 h.
Water (30 mL) was added and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by prep-HPLC to obtained product as a white solid (2.2 mg, yield: 3.3%). ESI-MS [M+H]+: 446.7. Purity: 100%. 1-HNMR (400 MHz, DM50): 6 8.62-8.50 (m, 2H), 8.47 (d, J = 8.0 Hz, 1H), 8.32 (s, 2H), 8.30 (s, 1H), 8.23 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.32 (s, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.57 (dd, J = 8.0, 2.0 Hz, 1H), 6.27 (s, 1H), 5.45 (s, 2H), 4.55 (d, J = 4.0 Hz, 2H), 1.99-1.93 (m, 1H), 1.02-0.95 (m, 2H), 0.78-0.70 (m, 2H).
Example 51 Scheme 51 ri NH, nn >-H(OF)2 ,..., v,L)' 1 ,,,,N NH2 CI 0,-.= i N2H,H,0 .1.'..Ø''''.\
N 0 CI 0,...--,,, _____________________________________________________ r ___________________ ).-Br''11 Pd(OAc),, K,PO4 Et0H, reflu, 16 h \--'--1\j, Et0H, reflu, 12 h SPhos. toluene/Hp 0"--\\
95 C,14 h NH, CI
,2õ.
,-, ¨Q 1,1 -,--N 0 0 TsCI, Et,, DCM \_.. 1:1--,õ..- \ LION IN---0,N \ 0L N-....%
)õ.õ,N, ________________________________________________________________________ ).-N'C)LIN'IlfLO
\---'-0 1,1 \ Me0H, I HF, H2o \ \ ¨c-HOBt, EDO
DIPEA, DMF
:,, 1=1-)2...0 1,1,----\
isek...111,õ1.......q I
[0299]
Synthesis of 5-cyclopropylpyridin-2-amine. To a solution of 5-bromopyridin-2-amine (50 g, 290 mmol) in toluene/H20 (700 mL/70 mL) was added cyclopropylboronic acid (37.4 g, 435 mmol), Pd(OAc)2 (6.49 g, 29.0 mmol), SPhos (12.8 g, 29.0 mmol) and K3PO4 (184.4 g, 870 mmol). The reaction mixture was stirred at 95 C for 14 h under nitrogen. Then the mixture was concentrated in vacuo. Water (400 mL) was added and the mixture was extracted with DCM (500 mL x 2). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (PE/Et0Ac = 1/1) to give the 5-cyclopropylpyridin-2-amine as a yellow solid (38 g, yield: 97%). ESI-MS
[M+H]+: 135.2.
[0300] Synthesis of ethyl 2-(6-cyclopropylimidazo11,2-a] pyridin-2-yl)acetate. To a solution 5-cyclopropy1-4-methylpyridin-2-amine (30 g, 223.9 mmol) in Et0H (400 mL) was added ethyl 4-chloro-3-oxobutanoate (110 g, 671.7 mmol) at RT. The resulting mixture was stirred at 90 C for 16 h and then concentrated in vacuo. H20 (500 mL) was added, the pH value of the mixture was adjusted to 8 by adding saturated NaHCO3 solution, and then the mixture was extracted with Et0Ac (400 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product, which was purified by silica gel chromatography (DCM/Me0H = 10/1) to give ethyl 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate (40 g, impure) as a black solid. ESI-MS [M+H]+: 245.2.
[0301] Synthesis of 2-(6-cyclopropylimidazo11,2-alpyridin-2-yl)acetohydrazide. A
mixture of ethyl 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate (40 g, impure) and N2H4-H20 (50 mL) in Et0H (300 mL) was stirred at 85 C for 12 h. The mixture was then concentrated and purified by silica gel chromatography (DCM/Me0H = 10/1) to give 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide (17.1 g, yield: 31.5% in 2 steps) as a yellow solid. ESI-MS [M+H]+: 231.1.
[0302] Synthesis of ethyl 2-(2-(2-(6-cyclopropylimidazo11,2-alpyridin-2-yl)acetyl)hydraziny1)-2-oxoacetate. To a solution of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide (17 g, 73.9 mmol) and DIPEA (38 mL, 222 mmol) in DCM (300 mL) was added ethyl 2-chloro-2-oxoacetate (15 g, 111 mmol) slowly at 0 C. The reaction mixture was stirred at RT for 2 h. Water (200 mL) was added and the mixture was extracted with DCM (200 mL x 2). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (DCM/Me0H = 10/1) to give (ethyl 2424246-cyclopropylimidazo[1,2-a] pyridin-2-yl)acetyl)hydraziny1)-2-oxoacetate (17 g, yield: 70%) as a yellow solid. ESI-MS [M+H]+: 331.1.
[0303] Synthesis of ethyl 54(6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxylate. To a solution of ethyl 2-(2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl) hydraziny1)-2-oxoacetate (17 g, 51.5 mmol) and Et3N (14 mL, 2 mmol) in DCM
(300 mL) was added a solution of TsC1 (11.8 g, 61.8 mmol) in DCM (50 mL) at RT. The reaction mixture was stirred at this temperature for 16 h. Water (200 mL) was added and the mixture was extracted with DCM (200 mL x 2). The combined organic layers were concentrated and purified by silica gel chromatography (DCM/Me0H = 10/1) to give 2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (8.2 g, yield: 51%) as a yellow oil. ESI-MS
[M+H]+: 313.2.
[0304] Synthesis of lithium 54(6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxylate. A solution of ethyl 5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole- 2-carboxylate (8.0 g, 25.6 mmol) and Li0H.H20 (2.1 g, 51.2 mmol) in a mixed solvent of THF/Me0H/H20 (50 mL/50 mL/50 mL) was stirred at RT
for 2 h.
THF and methanol were removed in vacuo at 20 C and the remaining H20 phase was lyophilized to give lithium 54(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate (7.4 g, yield: 100%) as a yellow solid. This material was used directly in the next step without further purification. ESI-MS [M+H]: 285.1.
[0305] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (I-51). A
mixture of lithium 546-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole- 2-carboxylate (7 g, 24 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (6.28 g, 28.8 mmol), EDCI (9.2 g, 48 mmol), HOBT (6.48 g, 48 mmol) and DIPEA (12 mL, 72 mmol) in DMF (100 mL) was stirred at 20 C for 48 h. The mixture was concentrated to remove DMF, diluted with DCM/Me0H (300 mL, 10/1 (v/v)) and washed with H20 (100 mL x 2).
The organic layer was separated, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (DCM/Me0H = 10/1) and then triturated with methanol to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-546-cyclopropylimidazo[1,2-a] pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide (3.1 g, yield: 28.7%) as a light yellow solid. ESI-MS [M+H]: 448.2. Purity: 99%. 111 NMR (400 MHz, DMS0): 6 9.73 (t, J
= 5.8 Hz, 1H), 8.32-8.29 (m, 3H), 7.83 (d, J = 1.0 Hz, 1H), 7.79 (s, 1H), 7.37 (d, J =
9.3 Hz, 1H), 6.98 (dd, J = 9.4, 1.7 Hz, 1H), 6.67 (dd, J = 7.4, 2.1 Hz, 1H), 4.62 (d, J = 5.9 Hz, 2H), 4.42 (s, 2H), 1.98-1.85 (m, 1H), 0.97-0.85 (m, 2H), 0.75-0.59 (m, 2H).
Example 52 Scheme 52 2a13 0 NH 1\1_-.-1 OH
EDCI, HOBt, D1PEA, DMF
1-52 Br [0306] Synthesis of N-((7-bromoimidazo[1,5-alpyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (1-52). A
mixture of 5((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylic acid (50 mg, 0.18 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (55 mg, 0.21 mmol), EDCI (70 mg, 0.35 mmol), HOBT (50 mg, 0.35 mmol) and DIPEA
(0.1 mL, 0.53 mmol) in DMF (3 mL) was stirred at 50 C for 16 h. Water (30 mL) was added and extracted with Et0Ac (30 mL x 3). The combined organic layers concentrated and purified by prep-HPLC to give N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-546-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide (3.0 mg, yield:
3.5%) as alight yellow solid. ESI-MS [M+H]+: 492.1. Purity: 96.8%. 111NMR (400 MHz, DMS0): 6 9.73 (t, J = 5.9 Hz, 1H), 8.32 (s, 2H), 8.25 (d, J = 7.4 Hz, 1H), 8.00 (s, 1H), 7.79 (s, 1H), 7.37 (d, J = 9.4 Hz, 1H), 6.98 (dd, J = 9.3, 1.7 Hz, 1H), 6.74 (dd, J =
7.4, 1.9 Hz, 1H), 4.62 (d, J = 5.9 Hz, 2H), 4.42(s, 2H), 1.95-1.89(m, 1H), 0.99-0.82 (m, 2H), 0.68-0.66(m, 2H).
Example 53 Scheme 53 N-n\I N=n\I
}-NH2 N
N,N1 4j1coll _____________________________ HATU, DIEA, DMF .. 1-53 [0307] Synthesis of N-((6-aminoimidazo[1,5-alpyridin-1-y1)methyl)-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-53). To a solution of 1((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (60 mg, 0.21 mmol), 1-(aminomethyl)imidazo[1,5-a]pyridin-6-amine (51 mg, 0.32 mmol) and HATU (120 mg, 0.31 mmol) in DNIF (5 mL) was added DIPEA (81 mg, 0.63 mmol).
The resulting reaction was stirred at RT for 12 h. H20 (25 mL) was added and the reaction was extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with prep-TLC
(DCM/Me0H = 10/1) to give the N46-aminoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (10 mg, yield: 11%) as a white solid. ESI-MS [M+H]+: 427.2. Purity: 92.3%. IENNIR (400 MHz, DMS0):
6 8.47 (t, J = 5.6 Hz, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 8.16-8.14 (m, 2H), 7.86 (s, 1H), 7.71 (s, 1H), 7.40-7.38 (m, 1H), 7.32 (s, 1H), 7.00-6.97 (m, 1H), 6.32-6.30 (m, 1H), 5.38 (s, 2H), 4.55 (d, J = 5.6 Hz, 2H), 1.95-1.78 (m, 2H), 0.95-0.83 (m, 4H), 0.70-0.60 (m, 4H).

Example 54 Scheme 54 CN
/*
Zn(CN)2,Pd(PPh3)4 CI
BrN NH2 DMF, 80 C, 3 h NC N NH2 DMF, 90 C, 2.5 h CI

H
HN
________________________ CN
Cs2CO3, DMF, rt, 2 h ____________ /1\T

[0308] Synthesis of 6-aminopicolinonitrile. To a solution of 6-bromopyridin-2-amine (500 mg, 2.9 mmol) in DMF (10 mL) was added Zn(CN)2 (480 mg, 4.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (335 mg, 0.29 mmol). The resulting mixture was stirred at 80 C under nitrogen for 3 h. The reaction mixture was filtered through celite and the filtrate was diluted with H20 (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give aminopicolinonitrile (250 mg, yield: 72%). ESI-MS [M+H]+: 120.1.
[0309] Synthesis of 2-(chloromethyl)imidazo[1,2-a] pyridine-5-carbonitrile. To a solution of 6-aminopicolinonitrile (200 mg, 1.67 mmol) in DMF (3 mL) was added 1,3-dichloropropan-2-one (1.0 g, 8.33 mmol). The resulting mixture was stirred at 90 C for 2.5 h.
The reaction mixture was diluted with H20 (50 mL), extracted with ethyl acetate (3 x 50 mL), The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give (chloromethyl)imidazo[1,2-a]pyridine-5-carbonitrile (150 mg, yield: 47%). ESI-MS [M+H]:
192Ø

[0310] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((5-cyanoimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-54). To a solution of 2-(chloromethyl)imidazo[1,2-a]pyridine-5-carbonitrile (44 mg, 0.23 mmol) in DMF (3 mL) was added cesium carbonate (224 mg, 0.69 mmol) amd N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (63 mg, 0.23 mmol). The resulting mixture was diluted with H20 (30 mL), extracted with ethyl acetate (3 x 50 mL), The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-HPLC to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-145-cyanoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (12.7 mg, yield: 12.8%).
ESI-MS [M+H]: 431.1. Purity: 99.08%. 1H NMR (400 MHz, DMS0): 6 8.59 (t, J =
5.8 Hz, 1H), 8.34-8.26 (m, 2H), 8.26 (s, 1H), 8.14 (s, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.87 (s, 1H), 7.84-7.79 (m, 1H), 7.79-7.77 (m, 1H), 7.41-7.35 (m, 1H), 6.67-6.62 (m, 1H), 5.50 (s, 2H), 4.56 (d, J =
5.7 Hz, 2H).
Example 55 Scheme 55 CN
Br 0 Br N
CN
111(N---/
) \)--"N Cs2CO3, DMF, rt, 2 h \)--N 1-55 [0311] Synthesis of N-((7-bromoimidazo11,5-a]pyridin-1-yl)methyl)-1-((5-cyanoimidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-75). To a solution of 2-(chloromethyl)imidazo[1,2-a]pyridine-5-carbonitrile (49 mg, 0.26 mmol) in DMF (3 mL) was added cesium carbonate (250 mg, 0.77 mmol) and N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (83 mg, 0.26 mmol).The resulting mixture was diluted with H20 (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer were washed with brine, dried over anhydrous sodium sulfate and concentrated.
The residue was purified by prep-HPLC to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-145-cyanoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (21 mg, yield: 17%). ESI-MS [M+H]+: 475.1. Purity: 97.73%. 1H NMR (400 MHz, DMS0): 6 8.59(t, J = 5.6 Hz, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.26-8.22 (m, 1H), 8.14 (s, 1H), 7.97-7.92 (m, 2H), 7.87 (s, 1H), 7.83-7.79 (m, 1H), 7.41-7.35 (m, 1H), 6.74-6.70 (m, 1H), 5.50 (s, 2H), 4.55 (d, J =
5.7 Hz, 2H).
Example 56 Scheme 56 N
N
N
N¨N\ CI 0 Br z H
1\I¨N
Cs2CO3, DMF, 50 C
NB

[0312] Synthesis of N-((7-bromoimidazo[1,5-alpyridin-1-yl)methyl)-1-((5-cyclopropylpyrazolo[1,5-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-56). A
mixture of 2-(chloromethyl)-5-cyclopropylpyrazolo[1, 5-a] pyridine (30 mg, 0.15 mmol), N-((7-bromoimidazo[1,5-a]pyridin-1-y1) methyl)-1H-pyrazole-4-carboxamide (48 mg, 0.15 mmol) and Cs2CO3 (200 mg, 0.61 mmol) in DIVIF (3 mL) was stirred at 50 C for 16 h.
Water (30 mL) was added and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by prep-HPLC to give N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-145-cyclopropylpyrazolo[1,5-a]pyridin-yOmethyl)-1H-pyrazole-4-carboxamide (10 mg, yield: 13%) as a white solid. ESI-MS [M+H]+:
490Ø Purity: 86.77%. 111 NMR (400 MHz, DMS0): 6 8.62-8.55 (m, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.32 (s, 1H), 8.25 (d, J = 0.8 Hz, 1H), 8.23 (s, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.87 (s, 1H), 7.32 (s, 1H), 6.72 (dd, J = 8.0, 2.0 Hz, 1H), 6.57 (dd, J = 8.0, 2.0 Hz, 1H), 6.27 (s, 1H), 5.45 (s, 2H), 4.55 (d, J = 4.0 Hz, 2H), 2.00-1.90 (m, 1H), 1.03-0.92 (m, 2H), 0.78-0.70 (m, 2H).

Example 57 Scheme 57 A.,......L.
...'"

.'-'= --N ''"- '...' --INI N,Na ,0_,/
THF/ethanol/H20, rt, 16 h .."-N N
Cs2CO3, DMF, rt N',3,OH
NH, N
[3 A.........L.
' ---- HC1 N --)--\
'..., N.......//
Cri N,---"N
________________ ).- N' N)\
...._õ...,1..., 1.,Q\
HATU, DIPEA, DMF, rt Br [0313] Synthesis of ethyl 1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-yl)methyl)-1H-pyrazole-4-carboxylate. A mixture of 5-chloro-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (190 mg, 0.79 mmol), ethyl 1H-pyrazole-4-carboxylate (221 mg, 1.58 mmol) and Cs2CO3 (769 mg, 2.36 mmol) in DMF (6 mL) was stirred at 60 C for 3 h.
Water (50 mL) was added and the mixture was extracted with Et0Ac (100 mL x 3).
The combined organic layers were concentrated and purified by silica gel chromatography (EA/PE =
2:3 to 10:1) to give ethyl 14(5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (220 mg, yield: 64%) as a white solid. ESI-MS [M+H]+:
345.2.
[0314] Synthesis of 1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid. To a solution of 1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (220 mg, 0.64 mmol) in a mixed solvent of ethanol/THF/H20 (3 mL/3 mL/1.5 mL) was added LiORH20 (107 mg, 2.55 mmol). The mixture was stirred at 60 C for 3 h. Most of the solvent was removed and the residue was diluted with H20 (10 mL), the pH value of mixture was adjusted to 4-5 by adding aqueous HC1 (1 M). The solution was extracted with Et0Ac (50 mL x 4). The combined organic layers were concentrated to give 1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (160 mg, yield: 80%) as a white solid. ESI-MS [M+H]+: 317.2.
[0315] Synthesis of N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-57). A
mixture of 1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (63.2 mg, 0.2 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (52.4 mg, 0.2 mmol), HATU (190 mg, 0.5 mmol) and DIPEA (77.5 mg, 0.6 mmol) in DMF (3 mL) was stirred at RT for 3 h. Water (30 mL) was added and the mixture was extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated and purified by prep-TLC (DCM: Me0H = 8:1) to give N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (19.9 mg, yield: 19%) as a white solid. ESI-MS [M+H]+: 524.1. Purity: 92.44%. 1H
NIVIR (400 MHz, DMS0): 6 8.58 (t, J = 5.6 Hz, 1H), 8.31 (s, 1H), 8.24-8.22 (m, 2H), 7.94-7.86 (m, 3H), 7.49 (d, J
= 9.3 Hz, 1H), 6.97 (d, J = 9.3 Hz, 1H), 6.71 (dd, J = 7.4, 1.8 Hz, 1H), 5.45 (s, 2H), 4.54 (d, J =
5.7 Hz, 2H), 2.14-2.09 (m 1H), 1.03-1.0 (m, 2H), 0.78-0.74 (m, 2H).
Example 58 Scheme 58 NH, q0 NH, NH, NH, NH, TMSCN, TEA HCOOH

0 m-CPBA 17 \ _________ ¨ DCM ¨ CH3CN, 105 C N \
)...- ¨0 N
, /N \
THF H,N ¨ 80 C, 2 h ¨NH ¨
-Cl Cl Cl Cl Cl ----s, --- ii N --- N
N NH, -DMF, POC13 Np......_,.......... Me0H, KOH
____________________________________________ 3.- OHC 3 __ -110 C, 2 h Ti(OEt)4, NaBH4, THF, 80 C, 12 h OH CI
CI
, , N NH, ss¨NH I HO, Me0H
--.1\
CI _________________ o- H,N I HATU DIPEA DMF

CI
[0316] Synthesis of 2-amino-4-chloropyridine 1-oxide. To a solution of 4-chloropyridin-2-amine (5.14 g, 40 mmol) in DCM (200 mL) at 0 C was added m-CPBA slowly.
The reaction mixture was stirred at RT for 4 h. Water (100 mL) was added and the pH of the mixture was adjusted to 8 by adding saturated NaHCO3 solution. Then the H20 layer was extracted with DCM/CH3OH (10:1, 100 mL x 5). The combined organic layers were concentrated to give 2-amino-4-chloropyridine 1-oxide (3.4 g, yield: 61%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H]:
145.1.
[0317] Synthesis of 6-amino-4-chloropicolinonitrile. A mixture of 2-amino-4-chloropyridine 1-oxide (1.74 g, 12 mmol), TMSCN (24 mL, 192 mmol) and TEA (26 mL, 192 mmol) in CH3CN (20 mL) was stirred at 105 C overnight in a sealed tube.
Saturated aqueous NaHCO3 was added to adjust the pH to 8, and then extracted with DCM (100 mL x 2). The combined organic layers were concentrated and purified by silica gel chromatography (EA/PE =
1/4) to give 6-amino-4-chloropicolinonitrile (1.16 g, yield: 63%) as a yellow solid. ESI-MS
[M+H]+: 154.1.
[0318] Synthesis of 6-(aminomethyl)-4-chloropyridin-2-amine. To a solution of 6-amino-4-chloropicolinonitrile (1.16 g, 7.6 mmol) in dry THF (10 mL) was added BH3 (1 M in THF, 19 mL) dropwise. The mixture was stirred at RT overnight. Then the mixture was quenched with CH3OH and stirred at RT for 1 h. the resulting mixture was then concentrated to give 6-(aminomethyl)-4-chloropyridin-2-amine (1.18 g, yield: 99%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H]+: 158.1.
[0319] Synthesis of N-((6-amino-4-chloropyridin-2-yl)methyl)formamide. A
solution of 6-(aminomethyl)-4-chloropyridin-2-amine (1.18 g, 7.5 mmol), HCOOH (20 mL) and Et0H
(20 mL) was stirred at 80 C for 2 h. Solvent was concentrated, H20 (20 mL) was added, and the pH of the mixture was adjusted to 8 by adding saturated aqueous NaHCO3 solution. The mixture was then extracted with Et0Ac (50 mL x 5). The combined organic layers were concentrated to give N-((6-amino-4-chloropyridin-2-yl)methyl)formamide (1.05 g, yield: 75%) as a white solid.
ESI-MS [M+H]: 186.1.
[0320] Synthesis of 7-chloroimidazo[1,5-alpyridin-5-amine. A solution of N-((6-amino-4-chloropyridin-2-yl)methyl)formamide (1.6 g, 8.6 mmol) in POC13 (15 mL) was stirred at 120 C for 2 h. Solvent was concentrated and the residue was diluted with H20 (20 mL). The pH of the mixture was adjusted to 8 by adding saturated NaHCO3 solution and then extracted with Et0Ac (100 mL x 3). The combined organics were concentrated and purified by silica gel chromatography (CH2C12/CH3OH = 10/1) to give 7-chloroimidazo[1,5-a]pyridin-5-amine (3.4 g, yield: 61%) as a gray solid. ESI-MS [M+H]: 168.1 [0321] Synthesis of N'-(7-chloro-1-formylimidazo11,5-alpyridin-5-y1)-N,N-dimethylformimidamide. A mixture of 7-chloroimidazo[1,5-a]pyridin-5-amine (155 mg, 0.92 mmol), DMF (203 mg, 2.76 mmol) and POC13 (3 mL) was stirred at 60 C for 1 h.
Then the reaction mixture was poured in to ice H20 and NH4OH was added to adjust pH to about 8. The resulting mixture was extracted with Et0Ac (30 mL x 5). The combined organic layers were concentrated to give N'-(7-chloro-1-formylimidazo[1,5-a]pyridin-5-y1)-N,N-dimethylformimidamide (220 mg, yield: 96%) as a yellow solid. ESI-MS [M+H]:
251.1.
[0322] Synthesis of 5-amino-7-chloroimidazo11,5-alpyridine-1-carbaldehyde. A
mixture of N'-(7-chloro-1-formylimidazo[1,5-a]pyridin-5-y1)-N,N-dimethylformimidamide (220 mg, 0.88 mmol), CH3OH (5 mL) and aqueous KOH (5 M, 1 mL) was stirred at RT
overnight.
Water (20 mL) was added and the mixture was extracted with Et0Ac (50 mL x 3).
The combined organic layers were concentrated and purified by silica gel chromatography (CH2C12/CH3OH = 9/1) to give 5-amino-7-chloroimidazo[1,5-a]pyridine-1-carbaldehyde (50 mg, yield: 29%) as an orange solid. ESI-MS [M+H]: 196.1.
[0323] Synthesis of N-((5-amino-7-chloroimidazo11,5-alpyridin-1-y1)methyl)-2-methylpropane-2-sulfinamide. A mixture of 5-amino-7-chloroimidazo[1,5-a]pyridine-1-carbaldehyde (22 mg, 0.11 mmol), 2-methylpropane-2-sulfinamide (15.7 mg, 0.13 mmol) and Ti(0E04 (0.12 mL, 0.55 mmol) in THF (0.2 mL) was stirred at 80 C overnight.
After cooled to RT, NaBH4 (20.8 mg, 0.55 mmol) was added. The reaction mixture was stirred at RT for 3 h.
Water (10 mL) and Et0Ac (10 mL) was added and the mixture was filtered. The filtration was extracted with Et0Ac (30 mL x 3). The combined organic layers were concentrated and purified by silica gel chromatography (CH2C12/CH3OH = 10/1) to give N-((5-amino-7-chloroimidazo[1,5-a]pyridin-l-yl)methyl)-2-methylpropane-2-sulfinamide (10 mg, yield: 30%) as a yellow solid.
ESI-MS [M+H]: 313.1.
[0324] Synthesis of 1-(aminomethyl)-7-chloroimidazo11,5-alpyridin-5-amine. To a solution of N45-amino-7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (48 mg, 0.16 mmol) in CH3OH (2 mL) was added HC1 (4 M in dioxane, 0.25 mL).
The mixture was stirred at RT for 1 h, then concentrated to give 1-(aminomethyl)-7-chloroimidazo[1,5-a]pyridin-5-amine (31 mg, yield: 99%) as a yellow solid which was used in the next step without purification. ESI-MS [M-16]+: 180.1.
[0325] Synthesis of N-((5-amino-7-chloroimidazo[1,5-alpyridin-1-y1)methyl)-1-((6-methylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-58). A
mixture of 1-(aminomethyl)-7-chloroimidazo[1,5-a]pyridin-5-amine (22 mg, 0.11 mmol), 1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (28 mg, 0.11 mmol), HATU (84 mg, 0.22 mmol), and DIPEA (43 mg, 0.33 mmol) in DMF (2 mL) was stirred at RT

for 2 h. Water (10 mL) was added and extracted with DCM/Me0H (30 mL x 3, 10/1, (v/v)). The combined organic layers were concentrated and purified by silica gel chromatography (DCM/CH3OH = 6/1) to give N-((5-amino-7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (9 mg, yield: 9%) as a white solid. ESI-MS [M+H]+: 435.2. Purity: 100%. 111 NMR (400 MHz, DMS0): 6 8.50 (t, J =
5.6 Hz, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.41 (d, J = 9.2 Hz, 1H), 7.10 (dd, J = 9.2, 1.3 Hz, 1H), 7.03 (d, J = 1.3 Hz, 1H), 6.84 (s, 2H), 5.64 (d, J = 1.8 Hz, 1H), 5.39 (s, 2H), 4.53 (d, J = 5.7 Hz, 2H), 2.24 (s, 3H).
Example 59 Scheme 59 >¨B(OFD2 0 NBS N Pd(0A02, PCy3, K3PO4 N.-) ICI
CH3CN, 0 C, 2 h H2N
dioxane Hs 100 C 16 h Hots! , õ DMF, 90 C, 2.5 h N¨% F

N N
Cs2CO3, DMF, rt, 2 h [0326] Synthesis of 6-fluoropyridin-2-amine. A mixture of 6-fluoropyridin-2-amine (3 g, 26.8 mmol) and N-bromosuccinimide (5.25 g, 29.5 mmol) in dry CH3CN (20 mL) was stirred at 0 C for 2 h. Water (100 mL) was added and the mixture was extracted with Et0Ac (100 mL x 3). The combined organic layers were concentrated and purified by silica gel chromatography (EA/PE = 1/5) to give 5-bromo-6-fluoropyridin-2-amine (4.31 g, yield: 84.2%) as a white solid.
ESI-MS [M+H]: 191Ø
[0327] Synthesis of 5-cyclopropy1-6-fluoropyridin-2-amine. A solution of 5-bromo-6-fluoropyridin-2-amine (3.0 g, 15.8 mmol), cyclopropylboronic acid (2.04 mg, 23.7 mmol), Pd(OAc)2 (354 mg, 1.58 mmol) , PCy3 (886.2 mg, 3.16 mmol) and K3PO4(6.7 g, 31.6 mmol) in dioxane/H20 (30 mL/3 mL) was stirred at 100 C for 16 h. Then the reaction mixture was diluted with H20 (50 mL) and extracted with Et0Ac (100 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated to give the desired compound 5-cyclopropy1-fluoropyridin-2-amine (yellow oil, 2.2 g). ESI-MS [M+H]+: 153.2.
[0328] Synthesis of 2-(chloromethyl)-6-cyclopropy1-5-fluoroimidazo11,2-al pyridine.
A solution of 5-cyclopropy1-6-fluoropyridin-2-amine (1.5 g, 10 mmol) and 1,3-dichloropropan-2-one (3.8 g, 30 mmol) in dry DMF (15 mL) was stirred at 90 C for 2.5 h. Then the reaction mixture was diluted with H20 (100 mL) and extracted with Et0Ac (100 mL x 3).
The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography (PE:EA = 5:1) to give the desired product 2-(chloromethyl)-6-cyclopropy1-5-fluoroimidazo[1,2-a]pyridine (325 mg, yield: 15%) as a yellow solid. ESI-MS [M+H]+: 225.1.
[0329] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yHmethyl)-1H-pyrazole-4-carboxamide (1-59).
A solution of 2-(chloromethyl)-6-cyclopropy1-5-fluoroimidazo[1,2-a]pyridine (22 mg, 0.1 mmol), N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (28 mg, 0.1 mmol), and Cs2CO3(98 mg, 0.3 mmol) in dry DNIF (2 mL) was stirred at RT for 2 h. Then the reaction mixture was diluted with H20 (20 mL) and extracted with Et0Ac (30 mL
x 3). The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography (DCM/Me0H = 15/1) to give the desired compound N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (17 mg, yield: 33%) as a yellow solid, ESI-MS [M+H]+:
446.2; [M/2 +H]+: 232.7. Purity: 97.80%. 111 NMR (400 MHz, DMS0): 6 8.57 (t, J = 5.7 Hz, 1H), 8.30-8.28 (m, 2H), 8.21 (s, 1H), 7.85 (d, J = 3.3 Hz, 2H), 7.76-7.76 (m, 1H), 7.33 (d, J
= 9.3 Hz, 1H), 7.04-7.00 (m, 1H), 6.63 (dd, J = 7.5, 2.1 Hz, 1H), 5.41 (s, 2H), 4.54 (d, J = 5.8 Hz, 2H), 2.04-2.00 (m, 1H), 0.97-0.94 (m, 2H), 0.76-0.72 (m, 2H).

Example 60 Scheme 60 N"\
,ANL.3 CI ________________ Br N
Cs2CO3, DMF, rt, 2 h Br [0330] Synthesis of N-((7-bromoimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yHmethyl)-1H-pyrazole-4-carboxamide (I-60).
A solution of 2-(chloromethyl)-6-cyclopropy1-5-fluoroimidazo[1,2-a]pyridine (22 mg, 0.1 mmol), N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (32 mg, 0.1 mmol), and Cs2CO3(98 mg, 0.3 mmol) in dry DIVIF (2 mL) was stirred at RT
for 2 h. Then the reaction mixture was diluted with H20 (10 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography (DCM/Me0H = 15/1) to give the desired compound N4(7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (11 mg, yield: 22%) as a yellow solid. ESI-MS [M+H]+:
508.1; [M/2 +H]+: 254.7. Purity: 91.63%. 1H Wit (400 MHz, DMS0): 6 8.58 (t, J = 5.7 Hz, 1H), 8.31 (s, 1H), 8.25-8.22 (m, 2H), 7.95 (s, 1H), 7.86 (d, J = 3.8 Hz, 2H), 7.34 (d, J =
9.3 Hz, 1H), 7.03 (t, J
= 8.8 Hz, 1H), 6.72 (dd, J = 7.4, 1.9 Hz, 1H), 5.43 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 2.05-2.01 (m, 1H), 0.98-0.95 (m, 2H), 0.82-0.65 (m, 2H).

Example 61 Scheme 61 OH
lz N 0 f----r- 'OH N 0, H N
CI Pd2(dba)3, B1NAP, Br --'-- Pd(dpp0C12, Na2CO3 Et0H, 70 C,16 h ---- 1 t-BuONa, toluene h. microwave 100 C, 16 h toluene.H20, 100"C,16 h ( OH
Br.õõ.11,11õ0 0 N NH, / HCI (2 M). I HF I - 0 0d)=\
I HF
SOCl2, DCM
LiAIH4, I
/ ).
Et0H, 85 C,18 h N , N CA N N

N NO
,õ
1 Cs2CO3, DMF. rt. 2 h --,.
....,0 ci.-----CN
\ , N

[0331] Synthesis of 5-cyclobuty1-2-methoxypyridine. A mixture of 5-bromo-2-methoxypyridine (4.0 g, 21.27 mmol), cyclobutylboronic acid (2.34 g, 23.40 mmol), Pd(dppf)C12 (1.55 g, 2.13 mmol) and Na2CO3 (2.93 g, 27.65 mmol) in toluene (100 mL) and H20 (20 mL) was stirred at 100 C for 16 h. The reaction mixture was concentrated, diluted with Et0Ac (100 mL) and filtered. The filtrate was washed with H20 (100 mL x 1) and brine (100 mL x 1), dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE =
1/60) to give 5-cyclobuty1-2-methoxypyridine (1.5 g, yield: 43%) as yellow oil. ESI-MS [M+H]+:
164.2.
[0332] Synthesis of 5-cyclobutylpyridin-2(1H)-one. A mixture of 5-cyclobuty1-2-methoxypyridine (1.5 g, 9.19 mmol) and HBr (15 mL, 40% (v/v) in H20) in Et0H
(6 mL) was stirred for at 80 C for 48 h. The reaction mixture was cooled to RT, concentrated, neutralized with NaHCO3 aqueous to adjust the pH to 7 and extracted with DCM/Me0H (60 mL x 3, 10/1 (v/v)). The combined organics was washed with brine (150 mL x 1), dried over Na2SO4, concentrated and purified by silica gel chromatography (EA) to give 5-cyclobutylpyridin-2(1H)-one (260 mg, yield: 19%) as a yellow syrup. ESI-MS [M+H]+: 150.2.
[0333] Synthesis of 2-chloro-5-cyclobutylpyridine. A solution of 5-cyclobutylpyridin-2(1H)-one (260 mg, 1.74 mmol) in POC13 (3 mL) was stirred at 130 C for 1 h under microwave.
The reaction mixture was concentrated and the residue was dissolved in Et0Ac (100 mL), washed with NaHCO3 aqueous (50 mL x 1) and brine (50 mL x 1), dried over Na2SO4, concentrated and then purified by silica gel chromatography (EA/PE = 1/50) to give 2-chloro-5-cyclobutylpyridine (250 mg, yield: 86%) as yellow oil. ESI-MS [M+H]: 168.1.
[0334] Synthesis of N-(5-cyclobutylpyridin-2-y1)-1,1-diphenylmethanimine.
A
mixture of 2-chloro-5-cyclobutylpyridine (220 mg, 1.31 mmol), diphenylmethanimine (357 mg, 1.97 mmol), Pd2(dba)3 (120 mg, 0.131 mmol), BINAP (163 mg, 0.262 mmol) and t-BuONa (315 mg, 3.28 mmol) in toluene (8 mL) was stirred at 100 C for 16 h. The reaction mixture was then diluted in Et0Ac (100 mL) and filtered. The filtrate was washed with H20 (50 mL x 1), dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE =
1/8) to give N-(5-cyclobutylpyridin-2-y1)-1,1-diphenylmethanimine (130 mg, yield: 32%) as a yellow solid.
ESI-MS [M+H]: 313.2.
[0335] Synthesis of 5-cyclobutylpyridin-2-amine. A mixture of N-(5-cyclobutylpyridin-2-y1)-1, 1-diphenylmethanimine (130 mg, 0.41 mmol) and HC1 (2 mL, 2 M) in THF (4 mL) was stirred at RT for 2 h. The reaction mixture was concentrated.
Water (20 mL) was added and the pH of the mixture was adjusted to 9 by adding saturated aqueous NaHCO3 solution. This resulting mixture was extracted with DCM/Me0H (50 mL x 3, 10/1 (v/v)). The combined organics was washed with brine (100 mL x 1), dried over Na2SO4, concentrated and purified by prep-TLC (EA) to give 5-cyclobutylpyridin-2-amine (35 mg, yield:
57%) as a yellow syrup. ESI-MS [M+H]: 149.2.
[0336] Synthesis of ethyl 6-cyclobutylimidazo[1,2-a]pyridine-2-carboxylate. The mixture of 5-cyclobutylpyridin-2-amine (28 mg, 0.19 mmol) and ethyl 3-bromo-2-oxopropanoate (41 mg, 0.20 mmol) in Et0H (5 mL) was heated to reflux and stirred for 18 h.
The reaction mixture was concentrated and the residue was dissolved in Et0Ac (20 mL), washed with NaHCO3 aqueous (20 mL x 1) and brine (20 mL x 1), dried over Na2SO4, concentrated and purified by silica gel chromatography (EA) to give ethyl 6-cyclobutylimidazo[1,2-a]pyridine-2-carboxylate (15 mg, yield: 33%) as a yellow solid. ESI-MS [M+H]: 245.2.
[0337] Synthesis of (6-cyclobutylimidazo[1,2-a]pyridin-2-yl)methanol. To a stirred solution of LiA1H4 (19 mg, 0.49 mmol) in THF (2 mL) was added dropwise the solution of 6-cyclobutylimidazo[1,2-a]pyridine-2-carboxylate (15 mg, 0.061 mmol) in THF (1 mL) at -78 C.
The mixture was stirred at -78 C for 30 min. The reaction mixture was then quenched with Na2SO4.10 H20 and filtered. The filtrate was washed with THF (10 mL) and concentrated to give (6-cyclobutylimidazo[1,2-a]pyridin-2-yl)methanol (8 mg, yield: 64%) as a yellow solid which was used in the next step without purification. ESI-MS [M+H]: 203.2.
[0338] Synthesis of 2-(chloromethyl)-6-cyclobutylimidazo11,2-al pyridine.
To a stirred solution of (6-cyclobutylimidazo[1,2-a]pyridin-2-yl)methanol (8 mg, 0.039 mmol) in DCM (1 mL) was added SOC12 (47 mg, 0.39 mmol) in DCM (0.5 mL). The mixture was stirred at RT for 1 h. The reaction mixture was concentrated to give 2-(chloromethyl)-6-cyclobutylimidazo[1,2-a]pyridine (10 mg, yield: 100%) as a yellow solid. ESI-MS [M+H]: 221.1.
[0339] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclobutylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-61).
The mixture of 2-(chloromethyl)-6-cyclobutylimidazo[1,2-a]pyridine (10 mg, 0.045 mmol), N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (12 mg, 0.045 mmol) and Cs2CO3 (30 mg, 0.09 mmol) in DIVIF (2 mL) was stirred at RT for 2 h. Water (10 mL) was added and the mixture was extracted with Et0Ac/THF (15 mL x 3, 5/1 (v/v)). The combined organic layers were washed with brine (40 mL x 3), dried over Na2SO4, concentrated and purified by prep-TLC (DCM/Me0H = 10/1) to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclobutylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (8 mg, yield: 38%) as a white solid. ESI-MS [M+H]: 460.2. Purity: 95.58%. 111NMR (400 MHz, DMS0): 6 8.57 (t, J
= 5.7 Hz, 1H), 8.34 (s, 1H), 8.30 (m, 2H), 8.20 (s, 1H), 7.86 (s, 1H), 7.77 (m, 2H), 7.44 (d, J =
9.3 Hz, 1H), 7.18 (dd, J = 9.3, 1.7 Hz, 1H), 6.64 (dd, J = 7.4, 2.1 Hz, 1H), 5.39 (s, 2H), 4.55 (d, J
= 5.8 Hz, 2H), 3.50 (m, 1H), 2.28 (m, 2H), 2.04 (m, 3H), 1.83 (m, 1H).
Example 62 Scheme 62 0-CL(3 NH Cl"--CliN CI ----0õ,c13 r CI jt....õCl CI
N
LloA,H40 DMF 95 C, 6 h Cs,CO3, DMF oc1 [0340] Synthesis of ethyl 2-(chloromethyl)imidazo[1,2-a]pyridine-5-carboxylate. A
mixture of ethyl 6-aminopicolinate (166 mg, 1.0 mmol) and 1, 3-dichloropropan-2-one (630 mg, 5.0 mmol) in dry DMF (10 mL) was stirred at 95 C for 6 h. Water (100 mL) was added and the mixture was extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated and purified by silica gel chromatography (EA/PE = 1/1) to give ethyl 2-(chloromethyl)imidazo[1,2-a]pyridine-5-carboxylate (70 mg, yield: 29%) as a yellow oil. ESI-MS [M+H]+: 239.1.
[0341] Synthesis of ethyl 2-((4-((7-chloroimidazo[1,5-a]pyridin-1-yl)methylcarbamoy1)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-5-carboxylate. A
mixture of ethyl 2-(chloromethyl)imidazo[1,2-a]pyridine-5-carboxylate (70 mg, 0.29 mmol), N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (80 mg, 0.29 mmol) and Cs2CO3 (270 mg, 0.87 mmol) in DMF (5 mL) was stirred at RT for 4 h. Water (30 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated and purified by prep-TLC (DCM/Me0H = 10/1) to give ethyl 2-((4-((7-chloroimidazo[1,5-a]pyridin-1-yl)methylcarbamoy1)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-5-carboxylate (90 mg, yield: 65%) as a yellow solid. ESI-MS [M+H]+: 478.1.
[0342] Synthesis of N-((7-chloroimidazo11,5-a]pyridin-1-yl)methyl)-1-45-(hydroxymethyl)imidazo11,2-a]pyridin-2-yHmethyl)-1H-pyrazole-4-carboxamide (1-62). To a solution of ethyl 2-((4-((7-chloroimidazo[1,5-a]pyridin-1-yl)methylcarbamoy1)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-5-carboxylate (30 mg, 0.06 mmol) in dry THF
(5 mL) was added LiA1H4 (7 mg, 0.18 mmol) at 0 C and the mixture was stirred at 0 C for 10 min. Water (10 mL) was added to quench the reaction and extracted with Et0Ac (30 mL x 3).
The combined organic layers were concentrated and purified by prep-TLC (DCM/Me0H = 10/1) to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-145-(hydroxymethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (16.5 mg, yield: 63.5%) as a light yellow solid. ESI-MS
[M+H]+: 436.1. Purity: 95.3%. 111 NMR (400 MHz, DMS0): 6 8.59 (s, 1H), 8.30 (d, J = 6.7 Hz, 2H), 8.23 (s, 1H), 7.84 (d, J = 9.7 Hz, 2H), 7.78 (s, 1H), 7.47 (d, J = 9.1 Hz, 1H), 7.33-7.20 (m, 1H), 6.91 (d, J = 6.6 Hz, 1H), 6.64 (dd, J = 7.5, 2.1 Hz, 1H), 5.67 (t, J =
5.7 Hz, 1H), 5.44 (s, 2H), 4.71 (d, J = 5.5 Hz, 2H), 4.55 (d, J = 5.8 Hz, 2H).

Example 63 Scheme 63 I N NH

DMF, 90 C, 2 h Cl/ N- "-C% cs2co3 T
-DMF, rt, 2 h 0 163 [0343] Synthesis of 2-(chloromethyl)-5-methoxyimidazo11,2-al pyridine. A
solution of 6-methoxypyridin-2-amine (500 mg, 4.1 mmol) and 1,3-dichloropropan-2-one (2.58 g, 20.5 mmol) in DMF (10 mL) was stirred at 90 C for 2 h. Then the reaction mixture was diluted with H20 (100 mL) and extracted with Et0Ac (100 mL x 3). The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography (CH2C12/Me0H =
3/1) to give the desired product 2-(chloromethyl)-5-methoxyimidazo[1,2-a]pyridine (200 mg, yield:
25%) as brown oil. ESI-MS [M+H]: 197.1.
[0344] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((5-methoxyimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-63). A
solution of 2-(chloromethyl)-5-methoxyimidazo[1,2-a]pyridine (36 mg, 0.18 mmol), N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (50 mg, 0.18 mmol) and Cs2CO3(235 mg, 0.72 mmol) in DMF (3 mL) was stirred at RT for 2 h. Water (30 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography (CH2C12/Me0H =
10/1) to give the desired compound N4(7-chloroimidazo[1,5-a]pyridin-1-y1)methyl)-1-((5-methoxyimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (20 mg, yield: 28%) as a white solid. ESI-MS [M+H]: 436.1. Puny: 96.0%. 111NMR (400 MHz, DMS0): 6 8.58 (t, J =
5.7 Hz, 1H), 8.32-8.27 (m, 2H), 8.22 (s, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.33-7.27 (m, 1H), 7.14 (d, J = 9.0 Hz, 1H), 6.66-6.62 (m, 1H), 6.35 (d, J = 7.4 Hz, 1H), 5.41 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 4.07 (s, 3H).

Example 64 Scheme 64 Cl N
OH
HATU, DIPEA, DMF
rt, 12h 1-64 [0345] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-64). To a solution of 1((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (128 mg, 0.5 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (141 mg, 0.65 mmol) and HATU (285 mg, 0.75 mmol) in DIVIF (10 mL) was added DIPEA (323 mg, 2.5 mmol). The resulting reaction was stirred at RT for 12 h. H20 (25 mL) was added to the reaction and extracted with Et0Ac (25 mL x 4). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with prep-TLC
(DCM/Me0H = 10/1) to give the N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (55 mg, yield: 26%) as a white solid. ESI-MS [M+H]+: 420.1. Purity: 96.6%. 'I-INN/IR (400 MHz, DMS0): 6 8.59 (s, 1H), 8.35-8.30 (m, 4H), 8.22 (s, 1H), 7.89 (s, 1H), 7.78-7.76 (m, 2H), 7.41 (d, J =
9.0 Hz, 1H), 7.11 (d, J = 9.0 Hz, 1H), 6.65 (d, J = 6.8 Hz, 1H), 5.39 (s, 2H), 4.55 (d, J = 5.2 Hz, 2H), 2.25 (s, 3H).

Example 65 Scheme 65 FfoHr 0 0 0 OBn 0 C DI, LDA, Rh 1101 0 -78 C. 2 h I FIN¨N
N1)¨\c, =VCrl)--\NN s2C DMF.1611 oBn Me0H,3 h NiN1¨\õ
H N
Pd/C N, 0H HATU. DIEA, rt rt 311 C rt 0 0 CI
Me0 0 Me0 0 Me0 0 I-65 [0346] Synthesis of 1-benzyl 6-methyl 3-oxohexanedioate. To a solution of benzyl acetate (1.5 g, 10 mmol) in THF(10 mL) was added LDA (1 M, 15 mmol) at -78 C
and stirred for 1 h (solution A). To a solution of 4-methoxy-4-oxobutanoic acid (1.58 g, 12 mmol) in THF
(10 mL) was added CDI (1.94 g, 12 mmol) and stirred at RT for 30 min (solution B). Solution B
was added to solution A at -78 C and stirred for another 2 h. Saturated NH4C1 (100 mL) was added to quenched the reaction and the reaction mixture was extracted with Et0Ac (100 mL x 3). The combined organics were concentrated and purified by silica gel chromatography (EA/PE
= 1/10) to give 1-benzyl 6-methyl 3-oxohexanedioate (500 mg, yield: 19%) as a colorless oil.
ESI-MS [M+H]: 265.1.
[0347] Synthesis of 1-benzyl 6-methyl (E)-2-((dimethylamino)methylene)-3-oxohexanedioate. A solution of 1-benzyl 6-methyl 3-oxohexanedioate (490 mg, 1.86 mmol) in DMFDMA (443 mg, 3.72 mmol) was heated to 80 C for 2 h. The resulting mixture was concentrated to give 1-benzyl 6-methyl (E)-2-((dimethylamino)methylene)-3-oxohexanedioate (600 mg, crude) as a yellow oil which was used in the next step without purification. ESI-MS
[M+H]+: 320.1.
[0348] Synthesis of benzyl 3-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylate.
To a solution of 1-benzyl 6-methyl (E)-2-((dimethylamino)methylene)-3-oxohexanedioate (600 mg, 1.86 mmol) in Me0H (6 mL) was added hydrazine hydrochloride (255 mg, 3.72 mmol). The mixture was stirred at RT for 16 h. The reaction was concentrated to give the crude, which was purified by silica gel chromatography (EA/PE = 1/1) to give benzyl 3-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylate (384 mg, yield: 64% for two steps) as a yellow oil.
ESI-MS [M+H]:
289.1.
[0349] Synthesis of benzyl 1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-3-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylate. To a solution of benzyl 3-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylate (90 mg, 0.31 mmol) and 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (78 mg, 0.38 mmol) in DIVIF (5 mL) was added CsCO3 (302 mg, 0.93 mmol) at RT. The mixture was stirred at RT for 16 h. The reaction was diluted with H20 (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by prep-TLC (Me0H/DCM = 1/15) to give benzyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylate (70 mg, yield:
50%) as a yellow oil. ESI-MS [M+H]: 459.1.
[0350] Synthesis of 1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-3-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylic acid. To a solution of benzyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylate (100 mg, 0.22 mmol) in Me0H (10 mL) was added Pd/C (10%, 30 mg).
The mixture was stirred at RT for 3 h under H2. The mixture was filtered and concentrated to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylic acid (67 mg, 83%) as a white solid. ESI-MS [M+H]: 369.1.
[0351] Synthesis of methyl 3-(4-(((7-chloroimidazo11,5-alpyridin-1-y1)methyl)carbamoy1)-1-((6-cyclopropylimidazo11,2-a]pyridin-2-y1)methyl)-1H-pyrazol-3-y1)propanoate (1-65). To a solution of 14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylic acid (80 mg, 0.22 mmol) and (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (56 mg, 0.26 mmol) in dry DMF
(4 mL) was added HATU (125 mg, 0.33 mmol) and DIPEA (114 mg, 0.88 mmol) at RT.
The reaction was stirred at RT for 3 h. Water (20 mL) was added and the mixture was extracted with Et0Ac (30 mL x 3). The organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated. The crude residue was purified by prep-TLC
(DCM/Me0H = 10/1) to give methyl 3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)propanoate (70 mg, yield: 61%) as a yellow solid. ESI-MS [M+H]+: 532.2. Purity: 95.2%. 1HNMR (400 MHz, DMS0):
6 8.53 (t, J = 5.7 Hz, 0.3H), 8.43-8.38 (m, 0.7H), 8.36-8.27 (m, 3H), 8.15 (s, 0.7H), 7.92 (s, 0.3H), 7.84-7.67 (m, 1.75H), 7.58 (s, 0.3H), 7.40-7.35 (m, 1H), 7.03-6.93 (m, 1H), 6.66-6.63 (m, 1H), 5.42 (s, 0.6H), 5.28 (s, 1.4H), 4.64-4.47 (m, 2H), 3.57-3.56 (m, 3H), 3.29-3.19 (m, 0.6H), 3.17-2.99 (m, 1.4H), 2.74-2.55 (m, 2H), 1.97-1.84 (m, 1H), 0.94-0.89 (m, 2H), 0.68-0.64 (m, 2H).
Example 66 Scheme 66 N = =N
HATU, DIEA lOy N
DMF, rt, 2 h [0352]
Synthesis of 1-((6-cyclopropylimidazo[1,2-alpyridin-2-yl)methyl)-N-((7-ethynylimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1-66). A
solution of 1((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (68 mg, 0.24 mmol), (7-ethynylimidazo[1,5-a]pyridin-1-yl)methanamine (50 mg, 0.24 mmol), HATU
(183 mg, 0.48 mmol) and DIPEA (93 mg, 0.72 mmol) in DIVIF (3 mL) was stirred at RT for 2 h.
Then the reaction mixture was diluted with H20 (50 mL) and extracted with Et0Ac (50 mL x 3).
The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography (CH2C12/Me0H = 10/1) to give the desired compound 14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-ethynylimidazo[1,5-a]pyridin-yl)methyl)-1H-pyrazole-4-carboxamide (40 mg, yield: 38%) as a white solid. ESI-MS [M+H]+:
436.2. Purity: 100%. 111 NMR (400 MHz, DMS0): 6 8.59 (t, J = 5.7 Hz, 1H), 8.34-8.31 (m,2H), 8.26-8.22 (m 1H), 8.20 (s, 1H), 7.88 (s, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.39 (d, J = 9.4 Hz, 1H), 7.01-6.97 (m, 1H), 6.59-6.55 (m, 1H), 5.38 (s, 2H), 4.58 (d, J = 5.8 Hz, 2H), 4.26 (s, 1H), 1.95-1.88 (m, 1H), 0.93-0.88 (m, 2H), 0.68-0.64 (m, 2H).

Example 67 Scheme 67 ,vC----...--N\
\ N& \N
N---...1/N N...." \,,, N
HATU, DIEA
0 DMF, rt, 2 h I-67 0 [0353] Synthesis of 1-((6-cyclopropylimidazo[1,2-alpyridin-2-yl)methyl)-N-((7-ethylimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1-67). A
solution of I-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (64 mg, 0.23 mmol), (7-ethylimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (49 mg, 0.23 mmol), HATU (175 mg, 0.46 mmol) and DIPEA (90 mg, 0.69 mmol) in DMF (3 mL) was stirred at RT
for 2 h. Then the reaction mixture was diluted with H20 (30 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography (CH2C12/Me0H = 10/1) to give the desired compound 14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-ethylimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (50 mg, yield: 49%) as a white solid. ESI-MS [M+H]:
440.2.
Purity: 97%. 1E1 NMIR (400 MHz, DMS0): 6 8.47 (t, J = 5.5 Hz, 1H), 8.32(s, 1H), 8.22-8.16(m, 3H), 7.86 (s, 1H), 7.71 (s, 1H), 7.42-7.32 (m, 2H), 7.01-6.96 (m, 1H), 6.52-6.48 (m, 1H), 5.38 (s, 2H), 4.56 (d, J= 5.6 Hz, 2H), 3.33-3.29 (m, 2H), 1.94-1.88 (m, 1H), 1.14 (t, J= 7.5 Hz, 3H), 0.93-0.88 (m, 2H), 0.69-0.63 (m, 2H).
Example 68 Scheme 68 _(NH2 Br .1\11) \ N......JN
nOH N
Nj\131\1-1 Q
HATU, DIPEA, DMF, rt, 2 h 1-68 Br [0354] Synthesis of N-((7-bromoimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-blpyridazin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-68). A
solution of 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (48 mg, 0.17 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (45 mg, 0.17 mmol), HATU (134 mg, 0.35 mmol) and DIPEA (65 mg, 0.53 mmol) in DMF
(3 mL) was stirred at RT for 2 h. Then the reaction mixture was diluted with H20 (30 mL) and extracted with Et0Ac (50 mL x 3). The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography (CH2C12/Me0H = 8/1) to give the desired compound N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1H-pyrazole-4-carboxamide (20 mg, yield: 24%) as a white solid. ESI-MS [M+H]+:
491.1. Purity: 93%. 1H NMR (400 MHz, DMS0): 6 8.56 (t, J = 5.7 Hz, 1H), 8.31 (s, 1H), 8.26-8.19 (m, 2H), 8.08 (s, 1H), 7.96-7.90 (m, 2H), 7.85 (s, 1H), 7.09 (d, J = 9.5 Hz, 1H), 6.74-6.69 (m, 1H), 5.41 (s, 2H), 4.54 (d, J = 5.7 Hz, 2H), 2.20-2.14 (m, 1H), 1.09-1.03 (m, 2H), 0.99-0.93 (m, 2H).
Example 69 Scheme 69 NH

CI 1\1"-"-=// CI 1-69 DMF, 95 C, 5 h Cs2CO3, ,1 NH
DMF, rt, 3 h ¨N
[0355] Synthesis of 2-(chloromethyl)imidazo[1,2-a] pyridine. A mixture of pyridin-2-amine (600 mg, 6.4 mmol) and 1, 3-dichloropropan-2-one (4.0 g, 32.0 mmol) in dry DMF (10 mL) was stirred at 95 C for 6 h. Water (100 mL) was added and the mixture was extracted with Et0Ac (80 mL x 3). The combined organic layers were concentrated and purified by silica gel chromatography (EA/PE = 1/1) to give 2-(chloromethyl)imidazo[1,2-a]pyridine (80 mg, yield:
7.5%) as a yellow oil. ESI-MS [M+H]+: 167.1.

[0356] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-(imidazo [1,2-alpyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide (1-69). A mixture of 2-(chloromethyl)imidazo[1,2-a]pyridine (80 mg, 0.48 mmol), N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (130 mg, 0.48 mmol) and Cs2CO3 (469 mg, 1.44 mmol) in DMF (5 mL) was stirred at RT for 3 h. Water (50 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layer were concentrated and purified by prep-TLC
(DCM/Me0H = 10/1) to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide (27 mg, yield: 14%) as a white solid. ESI-MS
[M+H]+: 406.2. Purity: 99.6%. 111 NMR (400 MHz, DMS0): 6 8.59 (t, J = 5.7 Hz, 1H), 8.51 (d, J = 6.8 Hz, 1H), 8.30 (d, J = 7.1 Hz, 2H), 8.23 (s, 1H), 7.85 (d, J = 14.5 Hz, 2H), 7.78 (s, 1H), 7.49 (d, J = 9.1 Hz, 1H), 7.27-7.18 (m, 1H), 6.87 (t, J = 6.7 Hz, 1H), 6.65 (dd, J = 7.4, 2.0 Hz, 1H), 5.42 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H).
Example 70 Scheme 70 \C)L1dYLO LIOH
S-t-OH
ACH. 50 C, 16 h \\/1\r Me0H, I FIF, 50 C, 1 h ,25,1aCI 0 EDCI, HOBt, DIPEA, 50 C, 16 h [0357] Synthesis of ethyl 5-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1,3,4-thiadiazole-2-carboxylate. A mixture of ethyl 2-(2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl)hydraziny1)-2-oxoacetate (330 mg, 1.0 mmol) and Lawesson's Regent (600 mg, 1.5 mmol) in CH3CN (20 mL) was stirred at 50 C for 16 h under N2. The mixture was concentrated and purified by silica gel chromatography (DCM/Me0H = 10/1) to give ethyl 54(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxylate (280 mg, yield:
85.4%) as a yellow oil. ESI-MS [M+H]+: 329.1 [0358] Synthesis of lithium 5-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1,3,4-thiadiazole-2-carboxylate. A solution of ethyl 546-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxylate (280 mg, 0.85 mmol) and Li0E11120 (70 mg, 1.70 mmol) in THF/Me0H/H20 (2 mL/2 mL/2 mL) was stirred at 50 C for 2 h. The mixture was concentrated to give lithium 546-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxylate (320 mg, crude) as a yellow solid. ESI-MS [M+H]+:
301.1.
[0359] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1,3,4-thiadiazole-2-carboxamide (I-70). A
mixture of 5((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxylic acid (100 mg, crude), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (72 mg, 0.33 mmol), EDCI (130 mg, 0.66 mmol), HOBT (90 mg, 0.66 mmol) and DIPEA (0.2 mL, 0.99 mmol) in DMF (4 mL) was stirred at 50 C for 16 h. Water (30 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated and purified by prep-HPLC to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-546-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxamide (12.1 mg, yield: 7.9%) as a light yellow solid. ESI-MS [M+H]+: 464.1. Purity: 95.4%. 1H NMR (400 MHz, DMS0): 6 9.62 (t, J = 5.9 Hz, 1H), 8.40 (s, 1H), 8.35-8.26 (m, 2H), 7.91-7.80 (m, 2H), 7.49 (d, J = 9.3 Hz, 1H), 7.13 (d, J = 9.4 Hz, 1H), 6.67 (dd, J = 7.5, 2.1 Hz, 1H), 4.74-4.48 (m, 4H), 1.99-1.93 (m, 1H), 1.00-0.88 (m, 2H), 0.71-0.69 (m, 2H).

Example 71 Scheme 71 >_13,0H
vr0 0 NH2 0 (i:1=% NB S C1C1 MeCN
NH2 Pd(0A02 DMF
Br 6 N PCY3,K3PO4 N
N\N

0 Cl \ \N
Cs2CO3, DMF
\C1 10,1c CI
[0360] Synthesis of ethyl 2-amino-5-bromonicotinate. To a solution of ethyl 2-aminonicotinate (500 mg, 3.00 mmol) in dry MeCN (20 mL) was added NBS (643 mg, 3.6 mmol) slowly at RT. The resulting mixture was stirred at RT for 1 h. The reaction was then quenched with H20 (30 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product of ethyl 2-amino-5-bromonicotinate (700 mg, yield: 95.2%) as a white solid, which was used in the next step without purification. ESI-MS [M+H]: 245Ø
[0361] Synthesis of ethyl 2-amino-5-cyclopropylnicotinate. A mixture ethyl 2-amino-5-bromonicotinate (700 mg, 2.85 mmol), cyclopropylboronic acid (728 mg, 8.5 mmol), Pd(OAc)2 (140 mg, 0.05 mmol), K3PO4 (3 g, 14.2 mmol) and PCy3 (0.3 g, 1.14 mmol) in dioxance/H20 (50 mL/5 mL) was stirred at 95 C for 12 h in N2. The resulting mixture was quenched with H20 (40 mL), extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried with Na2SO4 and concentrated in vacuo to give the crude, which was purified with silica gel chromatography with PE/EA (1/1) to give ethyl 2-amino-5-cyclopropylnicotinate (500 mg, 86% yield) as a white solid. ESI-MS [M+H]:
207.1. Purity:
95%.

[0362] Synthesis of ethyl 2-(chloromethyl)-6-cyclopropylimidazo11,2-al pyridine-8-carboxylate. To a solution of ethyl 2-amino-5-cyclopropylnicotinate (500 mg, 1.94 mmol) in DMF (10 mL) was added 1,3-dichloropropan-2-one (986 mg, 77.7 mmol) at 95 C
for 3 h. Water (50 mL) was added and the pH of the reaction was adjusted to 8 with NaHCO3 and then extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with silica gel chromatography (Et0Ac/PE = 1/2) to give ethyl 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (550 mg, yield: 65.3%) as a white solid. ESI-MS
[M+H]: 278.7.
Purity: 90%.
[0363] Synthesis of ethyl 2-44-(((7-chloroimidazo[1,5-al pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-al pyridine-8-carboxylate (I-71). A mixture of ethyl 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (173 mg, 0.6 mmol) in DMF (3 mL) was added N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (138 mg, 0.5 mmol) and Cs2CO3 (406 mg, 1.25 mmol). The resulting mixture was stirred at RT for 3 h. The reaction was quenched with H20 (30 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with prep-TLC (DCM/Me0H = 10/1) to give the ethyl 24(44(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (10 mg, yield: 3.2%) as a white solid. ESI-MS [M+H]: 518.2.
Purity: 91.3%. 111 NMR (400 MHz, DMS0): 6 8.63-8.49 (m, 2H), 8.31-8.29 (m, 2H), 8.21 (s, 1H), 7.89 (s, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.75 (s, 1H), 7.60 (d, J = 1.7 Hz, 1H), 6.64 (dd, J
= 7.5, 2.1 Hz, 1H), 5.45 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 2.03-1.96 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.00-0.86 (m, 2H), 0.75-0.59 (m, 2H).

Example 72 Scheme 72 v:o&
NaOH
:&
\ N,.., \N N ---:\ 4 Et0H/THF/H20 N \ N
¨

CI
[0364] Synthesis of 2-44-(((7-chloroimidazo[1,5-alpyridin-1-y1)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-alpyridine-8-carboxylic acid (1-72). To a solution of ethyl 2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (40 mg, 0.077 mmol) in Et0H/THF/H20 (2 mL/2 mL/1 mL) was added NaOH (0.5 mL, 1 M), then the reaction was stirred at RT for 1 h. Most of the solvent was removed and the residue was diluted with H20 (3 mL). The pH of mixture was adjusted to 4-5 by adding HC1 aqueous (1 M). The resulting mixture was concentrated to give the crude, which was purified by prep-HPLC to give 2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6 cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (9.7 mg, 26% yield) as a white solid. ESI-MS
[M+H]+: 490.1. Purity: 97.9%. 1E1 NMR (400 MHz, DMS0): 6 8.66-8.54 (m, 2H), 8.34-8.27 (m, 2H), 8.25 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.79-7.74 (m, 1H), 7.70 (d, J =
1.7 Hz, 1H), 6.64 (dd, J = 7.5, 2.1 Hz, 1H), 5.49 (s, 2H), 4.56 (d, J = 5.7 Hz, 2H), 2.08-2.00 (m, 1H), 0.99-0.94 (m, 2H), 0.74-0.70 (m, 2H).
Example 73 Scheme 73 N
,vcr.) \ /
1\ff ). , N \ Na0H, Me0Hõ....
g o ci o CI
Me04 1-73 HO o [0365]
Synthesis of 3-(4-(((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)carbamoy1)-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazol-3-y1)propanoic acid (1-73).
To a solution of methyl 3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-y1)propanoate (53 mg, 0.1 mmol) in Me0H/H20 (2 mL/0.5 mL) was added aqueous NaOH (4 M, 0.1 mL). The reaction was stirred at RT for 4 h. The pH of mixture was adjusted to 4 by addin HC1 (1 M). After concentrating the mixture, the crude product was purified by prep-HPLC to give 3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)propanoic acid (40 mg, yield: 77%) as a white solid. ESI-MS
[M+H]: 518.1.
Purity: 97.7%. IIINNIR (400 MHz, DMS0): 6 9.31 (s, 2H), 8.37-8.24 (m, 3H), 8.03 (s, 1H), 7.80 (d, J = 1.0 Hz, 1H), 7.71 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 6.99 (dd, J
= 9.4, 1.7 Hz, 1H), 6.63 (dd, J = 7.5, 2.1 Hz, 1H), 5.28 (s, 2H), 4.53 (d, J = 5.7 Hz, 2H), 2.89 (t, J = 7.3 Hz, 2H), 2.43 (t, J = 7.3 Hz, 2H), 1.95-1.88 (s, 1H), 0.96-0.85 (m, 2H), 0.68-0.64 (m, 2H).
Example 74 Scheme 74 Br MeMgBr Dess-Martin Ti(0E04, NaBH4 B
N Q/
THF, -60 C, 2 h Br Br DCM, THF, 80 C-rt, 20 h OH 0 C-rt, 0 d A
2 h N
N
HCl/Me0H
HCI __________________________________ rt, 2 h HATU, DIPEA, DMF, H
NH2 rt, 20 h 1-74 [0366]
Synthesis of 1-(7-bromoimidazo[1,5-alpyridin-1-yl)ethan-1-ol. To a solution of 7-bromoimidazo[1,5-a] pyridine-l-carbaldehyde (550 mg, 2.46 mmol) in THF (10 mL) was added methylmagnesium bromide (4.1 mL, 12.3 mmol) at -60 C. The mixture was stirred at -60 C for 2 h. LCMS confirmed the starting material consumed completely. Saturated ammonium chloride solution (30 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated salt H20 and concentrated. The residue was purified by flash column chromatography (ethyl acetate/petroleum ether from 0 to 20%) to give 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-ol (300 mg, yield:
51%) as a brown oil. ESI-MS [M+H]+: 241Ø
[0367] Synthesis of 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-one. To the solution of 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-ol (290 mg, 1.2 mL) in DCM (10 mL) was added Dess-Martin (1.0 g, 2.4 mmol) at 0 C, Then the reaction mixture was warmed to RT
and stirred for 2 h. Saturated sodium bicarbonate solution (40 mL) was added and the mixture was extracted with DCM (30 mL x 3). The combined organic layers were washed with saturated salt H20 and concentrated. The residue was purified by flash column chromatography (ethyl acetate/petroleum ether from 0 to 15%) to give 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-one (150 mg, yield: 52%) as a brown solid. ESI-MS [M+H]+: 239Ø
[0368] Synthesis of N-(1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethyl)-2-methylpropane-2-sulfinamide. To the mixture of 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-one (150 mg, 0.63 mmol) and 2-methylpropane-2-sulfinamide (92 mg, 0.76 mmol) in THF (5 mL) was added tetraethyl titanate (429 mg, 1.90 mmol). The mixture was stirred at 80 C for 18 hand cooled to RT. Sodium borohydride (120 mg, 3.15 mmol) was added and the mixture was stirred at RT for 2 h. Saturated ammonium chloride solution (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography (ethyl acetate/petroleum ether from 0 to 15%) to give N-(1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethyl)-2-methylpropane-2-sulfinamide (40 mg, yield: 18.5%) as a brown oil. ESI-MS [M+H]+: 344Ø
[0369] Synthesis of 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-amine hydrochloride. A mixture of N-(1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethyl)-2-methylpropane-2-sulfinamide (40 mg, 0.12 mmol) in HC1/Me0H (5 mL, 4 M) was stirred at RT for 2 h and concentrated to give 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-amine hydrochloride (30 mg, yield: 94%) which was used in the next step directly. ESI-MS [M+H]+: 240.0 [0370] Synthesis of N-(1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-74). To the solution of 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-amine hydrochloride (30 mg, crude) and 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (20 mg, 0.042 mmol) in dry DIVIF (3 mL) was added HATU (24 mg, 0.63 mmol) and DIPEA
(16 mg, 0.125 mmol) at RT. The reaction was stirred at RT for 18 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-HPLC to give N-(1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (4.4 mg, yield:
21%) as a white solid. ESI-MS [M+H]+: 504.1. Purity: 98.49%. 1HNMR (400 MHz, DMS0): 6 8.41 (d, J = 8.0 Hz, 1H), 8.33 (s, 1H), 8.31 (s, 1H), 8.27-8.19 (m, 2H), 7.89-7.85 (m, 2H), 7.72 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.02-6.97 (m, 1H), 6.72-6.67 (m, 1H), 5.49-5.40 (m, 1H), 5.38 (s, 2H), 1.96-1.87 m, 1H), 1.54 (d, J = 7.0 Hz, 3H), 0.94-0.88 (m, 2H), 0.69-0.63 (m, 2H).
Example 75 Scheme 75 HO

vl\rN
DIBAL-H
,v&N N, N
THF l CI

CI
[0371] Synthesis of N-((7-chloroimidazo[1,5-a1pyridin-1-yl)methyl)-1-46-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-75). A solution of ethyl 2444(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (40 mg, 0.074 mmol) in THF (3 mL) was added DIBAL-H (0.5 mL, 1 M) and the mixture was stirred at RT for 1 h. The reaction was quenched with saturated NH4C1 solution (10 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were concentrated to give the crude, which was purified by prep-HPLC to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-pyrazole-4-carboxamide (26.4 mg, 75% yield) as a white solid. ESI-MS [M+H]+:
476.2. Purity:
100%. 111 NMR (400 MHz, DMS0): 6 8.58 (t, J = 5.6 Hz, 1H), 8.31-8.29 (m, 2H), 8.21-8.19 (m, 2H), 7.87 (s, 1H), 7.78 (s, 1H), 7.69 (s, 1H), 7.00 (s, 1H), 6.64 (dd, J =
7.4, 2.0 Hz, 1H), 5.38 (s, 2H), 5.32 (t, J = 3.8 Hz, 1H), 4.74 (d, J = 3.8 Hz, 2H), 4.55 (d, J = 5.7 Hz, 2H), 1.97-1.90 (m, 1H), 0.97-0.86 (m, 2H), 0.70-0.60 (m, 2H).
Example 76 Scheme 76 N =AN
\ \N
N 'AN
A\rN CI Br ):$
N N CS2CO3, DMF, rt, 2 h Br [0372] Synthesis of N-((7-bromoimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-alpyrimidin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-76). A
mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine (40 mg, 0.19 mmol), N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (61 mg, 0.19 mmol), Cs2CO3(248 mg, 0.76 mmol) in DMF (2 mL) was stirred at RT for 2 h. Then the reaction mixture was diluted with H20 (30 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography (PE/EA = 10/1) to give the desired compound N-((7-bromoimidazo[1, 5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyrimidin-2-y1)methyl)-1H-pyrazole-4-carboxamide (25 mg, yield: 27%) as a white solid. ESI-MS [M+H]+: 491.1. Purity: 96.39%. lEINIVIR
(400 MHz, DMS0): 6 8.69 (d, J = 2.4 Hz, 1H), 8.59 (t, J = 5.7 Hz, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.32 (s, 1H), 8.27-8.20 (m 2H), 7.95 (d, J = 0.9 Hz, 1H), 7.87 (s, 1H), 7.63 (s, 1H), 6.75-6.69 (m, 1H), 5.43 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 2.02-1.93 (m, 1H), 1.02-0.92 (m, 2H), 0.79-0.70 (m, 2H).

Example 77 Scheme 77 OH

NaBH4. THF
0¨\
N =
H2N N NH, DMI-. reflux. 3 h DMI- 50 C, 4 h 50 C, overnight NH, NH
N
N
\

MsCl. DIPEA /OMs H NN
CI
I F11.. rt. 3 h NH CS2CO3. DMI-. 50 C, 3 h NH NN1-77 0 CI
[0373] Synthesis of ethyl 5-aminoimidazo[1,2-a]pyridine-2-carboxylate. A
mixture of pyridine-2,6-diamine (1.09 g, 10 mmol), ethyl 3-bromo-2-oxopropanoate (1.62 g, 8.3 mmol) in DMF (10 mL) was stirred at 90 C for 3 h. The mixture was concentrated to give crude ethyl 5-aminoimidazo[1,2-a]pyridine-2-carboxylate (2.7 g, yield: 100%) as a black solid, which was used in the next step without further purification. ESI-MS [M+H]+: 206.2.
[0374] Synthesis of ethyl (E)-5-(((dimethylamino)methylene)amino)imidazo[1,2-a]pyridine-2-carboxylate. A mixture of ethyl 5-aminoimidazo[1,2-a]pyridine-2-carboxylate (1.7 g, crude) and DMF-DMA (5 mL) in DNIF (5 mL) was stirred at 50 C for 3 h.
The mixture was diluted with H20 (50 mL), extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vecuo to give the crude, which was purified by silica gel chromatography (Me0H/DCM = 1/10) to give ethyl (E)-(((dimethylamino)methylene)amino)imidazo[1,2-a]pyridine-2-carboxylate (307 mg, yield: 14%) as a whilte solid. ESI-MS [M+H]+: 261.2.
[0375] Synthesis of (5-(methylamino)imidazo[1,2-a]pyridin-2-yl)methanol.
A mixture of ethyl (E)-5-(((dimethylamino)methylene)amino)imidazo[1,2-a]pyridine-2-carboxylate (217 mg, 0.83 mmol) and NaBH4 (314 mg, 8.3 mmol) in THF (10 mL) was stirred at 60 C overnight.
The mixture was then quenched with 1 M HC1 solution and filtered. The filtrate was concentrated to get a crude, which was purified by prep-TLC (Me0H/DCM = 1/3) to give (5-(methylamino)imidazo[1,2-a]pyridin-2-yl)methanol (52 mg, yield: 35%) as a white solid. ESI-MS [M+H]+: 178.2.

[0376] Synthesis of (5-(methylamino)imidazo11,2-alpyridin-2-yl)methyl methanesulfonate. To a solution of (5-(methylamino)imidazo[1,2-a]pyridin-2-yl)methanol (32 mg, 0.18 mmol) and DIPEA (70 mg, 0.54 mmol) in THF (10 mL) was added methanesulfonyl chloride (50.4 mg, 2.4 mmol). The mixture was stirred at RT for 3 h. Water (50 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated to give the (5-(methylamino)imidazo[1,2-a]pyridin-2-yl)methyl methanesulfonate, which was used into the next step without further purification. ESI-MS [M+H]+: 256.2.
[0377] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-45-(methylamino)imidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-77). A
mixture of (5-(methylamino)imidazo[1,2-a]pyridin-2-yl)methyl methanesulfonate (45.9 mg, crude), N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (50 mg, 0.18 mmol), and Cs2CO3 (596 mg, 1.8 mmol) in DMF (5 mL) was stirred at 50 C
for 3 h. Water (30 mL) was added to the reaction and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified by prep-HPLC (DCM/Me0H = 10/1) to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-(methylamino)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (5.2 mg, yield: 6.6%) as a whilte solid. ESI-MS [M+H]+: 435.2.
Purity: 96.21%. 111 NMR (400 MHz, DMS0): 6 8.59 (t, J = 5.6 Hz, 1H), 8.31-8.29 (m, 2H), 8.22 (s, 1H), 7.87 (s, 1H), 7.79-7.78 (m, 1H), 7.70 (s, 1H), 7.20-7.16 (m, 1H), 6.80-6.77 (m, 2H), 6.64 (dd, J = 7.4, 2.1 Hz, 1H), 5.80 (d, J = 7.4 Hz, 1H), 5.40 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 2.86 (d, J = 4.6 Hz, 3H).
Example 78 Scheme 78 Cs2CO3 N¨rsY

Toluene, 110 C, 16h Et0H, 70 C, 16 h DMF, 55 C, 16h 0 HC!
Me0H, HN
LiOH H20 (N17 HATU, DDI:
CI
rt, 16 11 - 0 DMF, rt, 16 h 0 [0378] Synthesis of methyl (Z)-2-(cyclopropanecarbony1)-3-(dimethylamino)acrylate. To a mixture of 3-cyclopropy1-3-oxo-propionic acid methyl ester (5 g, 35 mmol) in yoluene (20 mL) was added DMF-DMA (8 mL, 36.75 mmol). The resulting reaction was heated at 110 C for 16 h. After cooled to RT, the mixture was concentrated to give crude 2-cyclopropanecarbony1-3-dimethylamino-acrylic acid methyl ester (5.3 g, yield: 77%) as a white solid, which was used in the next step without further purification.
ESI-MS [M+H]+:
198.1.
[0379] Synthesis of methyl 3-cyclopropy1-1H-pyrazole-4-carboxylate. To a solution of methyl (Z)-2-(cyclopropanecarbony1)-3-(dimethylamino)acrylate (5.3 g, 27 mmol) in Et0H (20 mL) was added hydrazine hydrate (4 mL) dropwise. The reaction mixture was stirred at 70 C
for 16 h under N2 atmosphere. The reaction mixture was concentrated to give the residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give methyl 3-cyclopropy1-1H-pyrazole-4-carboxylate (2.9 g, yield 65%) as a white solid. ESI-MS
[M+H]+: 167.1.
[0380] Synthesis of methyl 3-cyclopropy1-14(6-cyclopropylimidazo11,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. To a solution of methyl 3-cyclopropy1-1H-pyrazole-4-carboxylate (200 mg, 1.20 mmol) in dry DMF (5 mL) was added 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (248 mg, 1.20 mmol) and Cs2CO3 (1.17 g, 3.6 mmol). Then the reaction mixture was stirred at 55 C for 16 h under N2 atmosphere. After cooling to RT, the reaction was diluted with H20 (50 mL), extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the residue, which was purified by silica gel column chromatography (DCM/methanol = 10/1) to give methyl 3-cyclopropy1-14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (390 mg, yield 96%) as a white solid.
ESI-MS [M+H]+:
337.4.
[0381] Synthesis of 3-cyclopropy1-1-((6-cyclopropylimidazo[1,2-a]pyridin-y1)methyl)-1H-pyrazole-4-carboxylic acid. To a solution of methyl 3-cyclopropy1-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (300 mg, 0.89 mmol) in methanol (5 mL) and H20 (5 mL) was added Li0H.H20 (187 mg, 4.45 mmol). The resulting reaction was stirred at 50 C for 16 h. Most of the solvent was removed and the residue was diluted with H20 (10 mL), the pH value of mixture was adjusted to 4-5 by adding HC1 (1 M).
The precipitate was collected and dried to give 3-cyclopropy1-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (230 mg yield 80%) as a white solid. ESI-MS [M+H]+: 323.1.
[0382] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-78). To a solution of 3-cyclopropy1-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (110 mg, 0.34 mmol) in dry DIVIF (3 mL) was added (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (148 mg, 0.68 mmol), HATU (194 mg, 0.51 mmol) and DIPEA (132 mg, 1.02 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with H20 (20 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4 and concentrated in vacuo to give a residue, which was purified by prep-TLC
(DCM/Me0H = 10/1) to afford N-((7-chloroimidazo[1, 5-a]pyridin-1-yl)methyl)-3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (47 mg, yield: 29%) as a white solid. ESI-MS [M+H] +: 486.2. Purity: 100%. IENNIR (400 MHz, DMSO-d6): 6 8.34-8.29 (m, 4H), 8.07 (s, 1H), 7.83-7.72 (m, 1H), 7.70 (s, 1H), 7.39 (d, J =
9.3 Hz, 1H), 6.99 (dd, J = 9.4, 1.7 Hz, 1H), 6.64 (dd, J = 7.5, 2.1 Hz, 1H), 5.24 (s, 2H), 4.53 (d, J = 5.7 Hz, 2H), 2.71-2.60 (m, 1H), 1.97-1.86 (m, 1H), 0.95-0.88 (m, 2H), 0.85-0.79 (m, 2H), 0.76-0.72 (m, 2H), 0.68-0.64 (m, 2H).
Example 79 Scheme 79 Hs fl N,1 0 ¨ \ NJ \N N="--;:\

1 1 CsCO3, DMF, rt CI
TMS

[0383] N-((7-chloroimidazo11,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-ethynyhmidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-79). To a solution of 2-(chloromethyl)-6-cyclopropy1-5-((trimethylsily1)ethynyl)imidazo[1,2-a]pyridine (30 mg, 0.1 mmol) and N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (27.5 mg, 0.1 mmol) in DMF (4 mL) was added Cs2CO3 (174 mg, 0.8 mmol). The reaction was stirred at RT for 4 h. The reaction mixture was concentrated to give the crude which was purified by prep-HPLC to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-ethynylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (7.7 mg, yield: 16.7%) as a pale solid. ESI-MS [M+H]+: 470.1. Purity: 100%. 11-1NMR (400 MHz, DMSO) 8.58 (t, J=
5.7 Hz, 1H), 8.33-8.27 (m, 2H), 8.22 (s, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.80-7.74 (m, 1H), 7.54 (d, J = 9.4 Hz, 1H), 6.81 (d, J = 9.5 Hz, 1H), 6.67-6.62 (m, 1H), 5.46-5.42 (m, 3H), 4.55 (d, J =
5.7 Hz, 2H), 2.30-2.22 (m, 1H), 1.12-1.01 (m, 2H), 0.85-0.75 (m, 2H).
Example 80 Scheme 80 c,----n-^-c, [>¨B(OH)2 Br i ,=-sI
________________ ).-- An-2>-1 DMSNOaN635 C __________________ ).--Pd(Ac0)2, SPhos ..- Et0H, 95 C, 13 h N
N NH2 K3P03, PhMe/H20 N NLL
95 C, 14 h N\
N\N 73 vCi CuSO4, sodium ascorbate H20/t-BuOH, RT, 3 h N x Li0H, THF/H20/Et0H
OH
N N

NH, HC]
CI IsCsr--/ N
N----.%N :: NI) N----'\
_______ 1.-- ki,.....),.,...Q1 \
HOBT, EDCI 1 N X
DMF, RT, 14 h 1-80 N

CI
[0384] Synthesis of 5-cyclopropylpyridin-2-amine. A mixture of 5-bromopyridin-2-amine (100 g, 585 mmol), cyclopropylboronic acid (60 g, 701 mmol), Pd(Ac0)2 (6.5 g, 29 mmol), SPhos (24 g, 58.5 mmol) and K3PO4 (372 g, 1.755 mol) in toluene/H20 (1.2 L/0.12 L) was stirred at 90 C for 14 h under N2. The reaction was concentrated in vacuo to give the crude, which was purified with silica gel chromatography (PE/EA = 1/2) to give the 5-cyclopropylpyridin-2-amine (61 g, yield: 78%) as a yellow solid. ESI-MS
[M+H]+: 135.1.
[0385] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo11,2-al pyridine. A mixture of 5-cyclopropylpyridin-2-amine (61 g, 455 mmol) and 1,3-dichloropropan-2-one (172 g, 1365 mmol) in Et0H (1 L) was stirred at 95 C for 13 h. The reaction was concentrated to remove the Et0H. The pH of the residue was adjusted to 9 by addition of aqueous NaHCO3 and extracted with Et0Ac (1 L x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with silica gel chromatography (EA) to give the 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, yield: 42%) as a yellow solid. ESI-MS [M+H]+: 207.1.
[0386] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo11,2-al pyridine.
To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, 193 mmol) in DMF
(600 mL) was added NaN3 (18.8 g, 290 mmol). The resulting reaction was stirred at RT for 2 h.
The reaction was diluted with H20 (500 mL) and extracted with Et0Ac (500 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with silica gel chromatography (PE/EA =
2/1) to give the 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, yield: 85%) as a yellow solid. ESI-MS [M+H]+: 214.1.
[0387] Synthesis of ethyl 14(6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-111-1,2,3-triazole-4-carboxylate. A mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, 163.5 mmol), ethyl propiolate (17.6 g, 180 mmol), CuSO4 (2.6 g, 16.35 mmol) and sodium ascorbate (3.3 g, 16.35 mmol) in H20/t-BuOH (150 mL/150 mL) was stirred at RT
for 3 h. Yellow solid was precipitated after 3 h and the mixture was filtered.
The cake was dried to give the ethyl 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (29 g, yield: 57%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H]+: 312.1.
[0388] Synthesis of 14(6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-111-1,2,3-triazole-4-carboxylic acid. A mixture of ethyl 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (29 g, 93.2 mmol) and LiOH (6.7 g, 279.6 mmol, solution in 50 mL H20) in THF/Et0H (150 mL/150 mL) was stirred at 50 C for 2 h. The reaction was concentrated to remove most of the solvent. The pH of the residue was adjusted to 4 by 2 N HC1 and a pink solid was precipitated out. The mixture was filtered and the filter cake was dried to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (20 g, 77%) as a pink solid. ESI-MS [M+H]+: 284.1.
[0389] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide (I-80). To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (10 g, 35.3 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (9.2 g, 42.4 mmol), HOBT (6.67 g, 49.42 mmol) and EDCI (9.5 g, 49.42 mmol) in DMF (500 mL) was added DIPEA (31.3 mL, 176.5 mmol). The resulting mixture was stirred at RT for 14 h. The reaction was poured into H20 (1 L) and yellow solid was precipitated out. The mixture was filtered and the cake was dried to give the crude, which was purified with silica gel chromatography (DCM/Me0H = 10/1) to give the N-((7-chloroimidazo[1,5-a]pyridin-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide (7.2 g, yield: 45.9%) as a white solid. HPLC Purity: 99.09% (214 nm), 99.18%
(254nm). LCMS m/z: 447.1 [M+H]+, tR = 1.098 (min). 1H Wit (400 MHz, DMS0): 6 8.91 (t, J
= 5.8 Hz, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 8.31-8.29 (m, 2H), 7.84-7.82 (m, 2H), 7.40 (d, J = 9.3 Hz, 1H), 7.01 (dd, J = 9.4, 1.7 Hz, 1H), 6.64 (dd, J = 7.5, 2.1 Hz, 1H), 5.72 (s, 2H), 4.62 (d, J =
5.9 Hz, 2H), 1.95-1.89 (m, 1H), 0.94-0.89 (m, 2H), 0.69-0.65 (m, 2H).
Example 81 Scheme 81 OH CI
Or TEA, Me0H. CO
N1)--\N SOCl2 N
v L\
DCM Pd(dppf)2Cl2 CI
[0390] Synthesis of N-((7-chloroimidazo 11,5-alpyridin-1-yl)methyl)-1-48-(chloromethyl)-6-cyclopropylimidazo [1,2-a] pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. To a solution of N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (80 mg, 0.17 mmol) in DCM (5 mL) was added SOC12 (0.5 mL, 1.7 mmol) slowly at 0 C. The resulting mixture was stirred at RT for 2 h. The reaction was concentrated in vacuo to give the crude, which was purified by silica gel chromatography (Et0Ac/PE = 2/1) to give methyl 2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)acetate (20 mg, yield: 24%) as a white solid. ESI-MS
[M+H]+: 494.2.
[0391] Synthesis of methyl 2-(24(4-(((7-chloroimidazo11,5-alpyridin-1-y1)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo11,2-alpyridin-8-y1)acetate (I-81). A mixture methyl 2-(24(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)acetate (40 mg, 0.08 mmol), Pd(dppf)2C12 (20 mg, 0.016 mmol), TEA (0.5 mL, 0.4 mmol) in Me0H (15 mL) was stirred at 55 C for 3 h under CO atmosphere. The reaction was monitored by LCMS
until the starting material consumed. The reaction was concentrated in vacuo to give the crude, which was purified by prep-HPLC to give methyl 2-(2444(7-chloroimidazo[1,5-a]pyridin-1-y1)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)acetate (22.7 mg, 55% yield) as a white solid. ESI-MS [M+H]+: 518.1. Purity: 95.6%. 11-1NMR (400 MHz, DMS0): 6 8.58 (t, J = 5.7 Hz, 1H), 8.34-8.28 (m, 2H), 8.25 (d, J = 1.3 Hz, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.80-7.74 (m, 1H), 7.66 (s, 1H), 6.94 (d, J = 1.2 Hz, 1H), 6.64 (dd, J = 7.4, 2.1 Hz, 1H), 5.38 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 3.89 (s, 2H), 3.57 (s, 3H), 1.94-1.87 (m, 1H), 0.94-0.89 (m, 2H), 0.69-0.60 (m, 2H).
Example 82 Scheme 82 0 Ho)Hr ' 0 0 0 0 0 OBn 0 1110 CDL LDA, H 0,11,..õ,1Hr0 DMF-DMA ellor H2rtNiN6H: 7...y.,....Aome F = 0 80 C, 211 -78 C, 2 I HN-N
,N
,v,/CNr1)-- \CI vONr7.1--\N_N
HATU, DIEA, DM N NH
Cs2CO3, DMF, rt 1611 Me0H, rt 3 11 0)fy rt 3 11 0 0 \
Me0 OBn Me0 OH

CI

[0392] Synthesis of 1-benzyl 6-methyl 3-oxohexanedioate. To a solution of benzyl acetate (1.5 g, 10 mmol) in THF (10 mL) was added LDA (1 M, 15 mmol) at -78 C
and stirred for 1 h (solution A). To a solution of 4-methoxy-4-oxobutanoic acid (1.58 g, 12 mmol) in THF
(10 mL) was added CDI (1.94 g, 12 mmol) and stirred at RT for 30 min (solution B). Solution B
was added to solution A at -78 C and stirred for another 2 h. Saturated NH4C1 (100 mL) was added to quenched the reaction and the reaction mixture was extracted with Et0Ac (100 mL x 3). The combined organics were concentrated and purified by silica gel chromatography (EA/PE
= 1/10) to give 1-benzyl 6-methyl 3-oxohexanedioate (500 mg, yield: 19%) as a colorless oil.
ESI-MS [M+H]: 265.1.
[0393] Synthesis of 1-benzyl 6-methyl (E)-2-((dimethylamino)methylene)-3-oxohexanedioate. A solution of 1-benzyl 6-methyl 3-oxohexanedioate (490 mg, 1.86 mmol) in DMF-DMA (443 mg, 3.72 mmol) was heated to 80 C for 2 h and then concentrated to give 1-benzyl 6-methyl (E)-2-((dimethylamino)methylene)-3-oxohexanedioate (600 mg, crude) as a yellow oil which was used in the next step without purification. ESI-MS [M+H]:
320.1.
[0394] Synthesis of benzyl 3-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylate.
To a solution of 1-benzyl 6-methyl (E)-2-((dimethylamino)methylene)-3-oxohexanedioate (600 mg, 1.86 mmol) in Me0H (6 mL) was added hydrazine hydrochloride (255 mg, 3.72 mmol). The mixture was stirred at RT for 16 h. The reaction was concentrated to give the crude, which was purified by silica gel chromatography (EA/PE = 1/1) to give benzyl 3-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylate (384 mg, yield: 64% for two steps) as a yellow oil.
ESI-MS [M+H]:
289.1.
[0395] Synthesis of benzyl 1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-5-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylate. To a solution of benzyl 3-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylate (90 mg, 0.31 mmol) and 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (78 mg, 0.38 mmol) in DMF (5 mL) was added Cs2CO3 (302 mg, 0.93 mmol) at RT. The mixture was stirred at RT for 16 h. The reaction was quenched with H20 (10 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were washed with brine, dried over Na2SO4, and the solvent is evaporated under reduced pressure to give a residue which was purified by prep-TLC (Me0H/DCM = 1/15) to give benzyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylate (30 mg, yield: 20%) as yellow oil. ESI-MS [M+H]+: 459.1.
[0396] Synthesis of 1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-5-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylic acid. To a solution of benzyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylate (100 mg, 0.22 mmol) in Me0H (10 mL) was added Pd/C (10%, 30 mg).
The mixture was stirred at RT for 3 h under H2. The reaction was filtrated and concentrated to give 14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylic acid (67 mg, 83%) as a white solid. ESI-MS [M+H]+: 369.1.
[0397] Synthesis of methyl 3-(4-(((7-chloroimidazo11,5-alpyridin-1-y1)methyl)carbamoy1)-1-((6-cyclopropylimidazo11,2-a]pyridin-2-y1)methyl)-1H-pyrazol-5-y1)propanoate (1-82). To a solution of 14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(3-methoxy-3-oxopropy1)-1H-pyrazole-4-carboxylic acid (80 mg, 0.22 mmol) and (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (48 mg, 0.26 mmol) in dry DMF
(4 mL) was added HATU (125 mg, 0.33 mmol) and DIPEA (114 mg, 0.88 mmol) at RT.
The reaction was stirred for 3 h. Water (30 mL) was added and the mixture was extracted with Et0Ac (50 mL x 3). The organic layers were washed with brine (80 mL), dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified by prep-HPLC
(DCM/Me0H =
10/1) to give methyl 3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-5-yl)propanoate (15.4 mg, yield:
13%) as a yellow solid. ESI-MS [M+H]+: 532.2. Purity: 98.7%. 1HNMR (400 MHz, DMS0): 6 8.70-8.54 (m, 2H), 8.48 (s, 1H), 8.34 (dd, J = 7.5, 0.8 Hz, 1H), 8.04-8.01 (m, 2H), 7.87-7.79 (m, 1H), 7.74 (d, J = 9.3 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 6.72 (dd, J = 7.5, 2.1 Hz, 1H), 5.66 (s, 2H), 4.61 (d, J = 5.7 Hz, 2H), 3.58 (s, 3H), 3.33-3.24 (m, 2H), 2.69-2.59 (m, 2H), 2.13-1.97 (m, 1H), 1.09-0.97 (m, 2H), 0.81-0.69 (m, 2H).

Example 83 Scheme 83 NH, 2 HN)y, HO)*
F 1. Ti(01-Pr), THF
_______ I POBr3, CH3CN I
I POC13, DNIF
\ reflux 3 h 0 ________________________________________________________________________ HATU, D1EA, DNIF reflux, 3h 100 C, 1 h 2. NaBH4, rt, 5 h Br rt, 3 h Br Br Br Br F
H HC1 in Me01-1)._ HATU, D1EA, ¨ rj\ F
N H N
rt, 1 h I NH2 0 "3 Br Br [0398] Synthesis of N-((4-bromopyridin-2-yl)methyl)-2,2-difluoroacetamide. To a mixture of (4-bromopyridin-2-yl)methanamine (500 mg, 2.67 mmol), DIPEA (1.7 g, 13.4 mmol) and 2, 2-difluoroacetic acid (256 mg, 2.67 mmol) in DMF (10 mL) was added HATU
(2.0 g, 5.34 mmol). The mixture was stirred at RT for 3 h. Water (100 mL) was added and the mixture was extracted with Et0Ac (100 mL x 3). The combined organics were washed with brine, dried over Na2SO4 and concentrated to give the crude, which was purified by silica gel chromatography (EA/PE = 1/2) to give N-((4-bromopyridin-2-yl)methyl)-2, 2-difluoroacetamide (400 mg, yield: 56%) as a yellow oil. ESI-MS [M+H]+: 265.0 [0399] Synthesis of 7-bromo-3-(difluoromethyl)imidazo[1,5-a] pyridine. To a solution of N-((4-bromopyridin-2-yl)methyl)-2, 2-difluoroacetamide (400 mg, 1.5 mmol) in CH3CN (10 mL) was added POBr3 (2.2 g, 7.5 mmol), The mixture was heated to reflux for 3 h. After cooled to RT, H20 (50 mL) was added and extracted with Et0Ac (50 mL x 4). The organic layers were dried over Na2SO4 and concentrated to give the crude, which was purified by silica gel chromatography (EA/PE = 1/2) to give 7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridine (180 mg, yield: 49%) as a yellow oil. ESI-MS [M+H]+: 247Ø
[0400] Synthesis of 7-bromo-3-(difluoromethyl)imidazo[1,5-a] pyridine-1-carbaldehyde. To a solution of 7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridine (180 mg, 0.73 mmol) in DMF (3 mL) was added POC13 (223 mg, 1.46 mmol). The mixture was stirred at 100 C for 1 h. After cooled to RT, H20 (30 mL) was added and extracted with Et0Ac (50 mL x 3). The organic phase was dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE = 1/2) to give 7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridine-1-carbaldehyde (100 mg, yield: 50%) as a yellow oil. ESI-MS [M+H]+: 275Ø
[0401] Synthesis of N-07-bromo-3-(difluoromethyl)imidazo11,5-alpyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide. To a solution of 7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridine-1-carbaldehyde (100 mg, 0.36 mmol) and methylpropane-2-sulfinamide (65 mg, 0.54 mmol) in THF (5 mL) was added Ti(Oi-Pi)4 (305 mg, 1.08 mmol). The mixture was refluxed for 3 h. After cooled to RT, NaBH4 (69 mg, 1.8 mmol) was added. The mixture was stirred at RT for 5 h. The reaction was then quenched with H20 (20 mL) and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the residue, which was purified by prep-TLC (Me0H/DCM = 1/25) to give N-((7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (100 mg, yield: 73%) as a yellow oil. ESI-MS [M+H]+: 380Ø
[0402] Synthesis of (7-bromo-3-(difluoromethyl)imidazo11,5-alpyridin-1-yl)methanamine. A mixture of N4(7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (100 mg, 0.26 mmol) in HC1 (4 M
solution in Me0H, mL) was stirred at RT for 1 h. The reaction was concentrated to give (7-bromo-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methanamine (60 mg, 83%) as a white solid, which was used in the next step without further purification. ESI-MS [M+H]: 276Ø
[0403] Synthesis of N-07-bromo-3-(difluoromethyl)imidazo11,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo11,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-83). To a solution of (7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methanamine (40 mg, 0.15 mmol) and 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (49 mg, 0.17 mmol) in dry DIVIF (3 mL) was added HATU (83 mg, 0.22 mmol) and DIPEA (75 mg, 0.58 mmol) at RT. The reaction was stirred at RT for 5 h.
Water (20 mL) was added and the mixture was extracted with Et0Ac (25 mL x 3).
The organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (DCM/Me0H
= 10/1) to give N47-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (6 mg, yield: 8%) as a yellow solid. ESI-MS [M+H]+: 540.1. Purity: 71.3%. 1HNMR (400 MHz, DMS0):
6 8.68 (t, J = 5.5 Hz, 1H), 8.46 (s, 1H), 8.33 (d, J = 7.4 Hz, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.90-7.87 (m, 2H), 7.61-7.48 (m, 2H), 7.25 (d, J = 8.7 Hz, 1H), 7.00 (dd, J = 7.5, 1.8 Hz, 1H), 5.49 (s, 2H), 4.59 (d, J = 5.6 Hz, 2H), 1.99-1.94 (m, 1H), 1.06-0.86 (m, 2H), 0.72-0.69 (m, 2H).
Example 84 Scheme 84 H2N , N
I
.......) 0 H H is SOC12, Me0H 3.... CI 1 s, N/ 0¨ TsCI, NaH,THF
Pd(0Ae)2, PPIt3, Et;N, CN)---/ 0 reflux, 5 h N 0 0 C, CI DMF, 100 C, 16 h Pd(0Ae)2, PC3,3,1{31'04, s, Isirs (3 LiAIH4, THF sõ Zs OH SOC12, DCM
toluene, H20, 90 C, 16 h j'... LNO -78 C, 2 h Nr. 0 C-rt, 1 h N
CI
0 CI Ts 1-1 --- , I / N --;--\ Li0H,,0, Me0H, I
Ell A N=.---\
Cs2CO3, DMF, 50C, 2 h rt, 2 h N o.- N
______________ ).-- N ...... -Nf \ 1-1 NrN3_ /1 ......)........

CI
CI
[0404] Synthesis of 6-chloro-1H-pyrrolo13,2-131pyridine-2-carboxylic acid. A mixture of 2,5-dichloropyridin-3-amine (2.0 g, 12.27 mmol), 2-oxopropanoic acid (3.24 g, 36.81 mmol), Pd(OAc)2 (551 mg, 2.45 mmol), PPh3 (2.57 g, 9.82 mmol) and Et3N (4.97 g, 49.08 mmol) in DMF (30 mL) was stirred at 100 C for 16 h. The reaction mixture was concentrated to give a crude which was purified by silica gel chromatography (DCM/Me0H = 5/1) to give 6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (2.41 g, yield: 100%) as a yellow solid. ESI-MS
[M+H]+: 197Ø
[0405] Synthesis of methyl 6-chloro-1H-pyrrolo13,2-131pyridine-2-carboxylate. To a stirred solution of 6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (2.41 g, 12.27 mmol) in Me0H (80 mL) was added SOC12 (4.38 g, 36.81 mmol) at RT. The mixture was stirred at 80 C
for 5 h. The reaction mixture was concentrated to give the residue, which was dissolved in Et0Ac (100 mL) and washed with NaHCO3 (100 mL) and brine (100 mL), dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE = 1/5) to give methyl 6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (1.0 g, yield: 39%) as a yellow solid.
ESI-MS [M+H]+:
211.1.
[0406] Synthesis of methyl 6-chloro-1-tosy1-111-pyrrolo13,2-131pyridine-2-carboxylate. To a stirred solution of NaH (42 mg, 1.04 mmol) in THF (4 mL) was added the solution of 6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (200 mg, 0.95 mmol) in THF (1 mL) at 0 C. After stirring for 20 min, a solution of TsC1 (199 mg, 1.04 mmol) in THF (1 mL) was added thereto at 0 C. The resulting mixture was stirred at 0 C for another 2 h. The reaction mixture was quenched with 1 M HC!, diluted with H20 (20 mL) and extracted with Et0Ac (25 mL x 3). The combined organics were washed with NaHCO3 (20 mL), brine (80 mL), dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE = 1/5) to give methyl 6-chloro-1-tosy1-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (240 mg, yield: 69%) as a yellow solid.
ESI-MS [M+H]: 365.1.
[0407] Synthesis of methyl 6-cyclopropy1-1-tosyl-111-pyrrolo13,2-131pyridine-2-carboxylate. A mixture of methyl 6-chloro-1-tosy1-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (240 mg, 0.658 mmol), cyclopropylboronic acid (170 mg, 1.97 mmol), Pd(OAc)2 (15 mg, 0.0658 mmol), tricyclohexyl phosphine (37 mg, 0.132 mmol) and K3PO4 (489 mg, 2.30 mmol) in toluene (10 mL) and H20 (2 mL) was stirred at 100 C for 16 h. The reaction mixture was filtered and washed with Et0Ac (50 mL). The combined filtrate was washed with H20 (50 mL x 1) and brine (50 mL x 1), dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE = 1/3) to give methyl 6-cyclopropy1-1-tosy1-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (180 mg, yield: 74%) as a yellow solid. ESI-MS [M+H]: 371.1.
[0408] Synthesis of (6-cyclopropy1-1-tosyl-111-pyrrolo13,2-131pyridin-2-y1)methanol.
To a stirred solution of LiA1H4 (74 mg, 1.94 mmol) in THF (5 mL) was added the solution of methyl 6-cyclopropy1-1-tosy1-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (180 mg, 0.486 mmol) in THF (1 mL) at -78 C dropwise. The mixture was stirred at -78 C for 2 h. The reaction mixture was quenched with Na2SO4.10H20 and filtered. The filtrate was concentrated and dried to give (6-cyclopropy1-1-tosy1-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol (105 mg, yield:
63%) as a yellow solid. ESI-MS [M+H]+: 343.1.
[0409] Synthesis of 2-(chloromethyl)-6-cyclopropy1-1-tosyl-1H-pyrrolo 13,2-b1pyridine. To a stirred solution of (6-cyclopropy1-1-tosy1-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol (105 mg, 0.307 mmol) in DCM (10 mL) was added the solution of SOC12 (182 mg, 1.53 mmol) in DCM (1 mL) at 0 C dropwise. The mixture was stirred at RT for 1 h. The reaction mixture was concentrated to give the residue, which was dissolved in Et0Ac (40 mL) and washed with NaHCO3 (40 mL) and brine (40 mL), dried over Na2SO4, concentrated and dried in vacuo to give 2-(chloromethyl)-6-cyclopropy1-1-tosyl-1H-pyrrolo[3,2-b]pyridine (110 mg, yield: 99%) as a yellow syrup. ESI-MS [M+H]: 361.1.
[0410] Synthesis of N-((7-chloroimidazo[1,5-a1pyridin-1-yl)methyl)-1-((6-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridin-2-yHmethyl)-1H-pyrazole-4-carboxamide. A
mixture of 2-(chloromethyl)-6-cyclopropy1-1-tosyl-1H-pyrrolo[3,2-b]pyridine (110 mg, 0.305 mmol), N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (70 mg, 0.254 mmol) and Cs2CO3 (248 mg, 0.762 mmol) in DMF (5 mL) was stirred at 50 C
for 2 h.
The reaction mixture was poured into H20 (40 mL) and extracted with Et0Ac/THF
(50 mL x 3, 5/1 (v/v)). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by prep-TLC (DCM/Me0H = 10/1) to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (38 mg, yield: 25%) as a yellow solid. ESI-MS [M+H]:
600.1.
[0411] Synthesis of N-((7-chloroimidazo11,5-a1pyridin-1-yl)methyl)-1-((6-cyclopropyl-1H-pyrrolo13,2-blpyridin-2-yHmethyl)-1H-pyrazole-4-carboxamide (1-84). A
mixture of N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (35 mg, 0.0583 mmol) and Li0H.E120 (307 mg, 7.30 mmol) in Me0H/H20 (2 mL/0.5 mL) was stirred at RT for 2 h. The reaction was concentrated in vacuo to remove the Me0H. And the residue was diluted in H20 (15 mL) and extracted with Et0Ac (30 mL x 3). The combined organics were washed with brine (90 mL), dried over Na2SO4, concentrated and purified by prep-TLC (DCM/Me0H =
7/1) to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-1H-pyrrolo[3,2-b]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (12 mg, yield: 46%) as a white solid. ESI-MS [M+H]+: 446Ø Purity: 97.56%. 1H NMR (400 MHz, DMS0): 6 11.22(s, 1H), 8.59(t, J =
5.4 Hz, 1H), 8.30 (m, 2H), 8.18 (d, J = 20.8 Hz, 2H), 7.90 (s, 1H), 7.77 (s, 1H), 7.28 (s, 1H), 6.64 (d, J = 7.3 Hz, 1H), 6.45 (s, 1H), 5.47 (s, 2H), 4.55 (d, J = 5.5 Hz, 2H), 2.01 (m, 1H), 0.96 (m, 2H), 0.68 (m, 2H).
Example 85 Scheme 85 HC1 "

,cF1/ N N
Br N HATU, DIEA N H N
N Br N
0 DMF, rt, 16 h 0 [0412]
Synthesis of N-((7-bromoimidazo[1,5-alpyridin-1-yl)methyl)-3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-85). To a solution of 3-cyclopropy1-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (50 mg, 0.16 mmol), in dry DMF (5 mL), was added (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (54 mg, 0.21 mmol), HATU (91 mg, 0.24 mmol) and DIPEA (62 mg, 0.48 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture diluted with H20 (20 mL) and extracted with ethyl acetate (30 mL x 3).
The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-TLC (DCM/Me0H = 10:1) to afford N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-3-cyclopropyl-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (30 mg, yield: 36%) as a white solid. ESI-MS [M+H]+: 532.2. Purity: 99.12%. 111 NMR (400 MHz, DMSO-d6): 6 8.33 (m, 3H), 8.24 (d, J
= 7.4 Hz, 1H), 8.07 (s, 1H), 7.94 (d, J = 0.8 Hz, 1H), 7.70 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 6.99 (dd, J = 9.4, 1.6 Hz, 1H), 6.71 (dd, J = 7.4, 1.9 Hz, 1H), 5.24 (s, 2H), 4.53 (d, J = 5.7 Hz, 2H), 2.67-2.61 (m, 1H), 1.93-1.88 (m, 1H), 0.94-0.89 (m, 2H), 0.85-0.80 (m, 2H), 0.75-0.73 (m, 2H), 0.69-0.64 (m, 2H).

Example 86 Scheme 86 0 ....,N
N "AN
1\fjcl\-11q NaOH M 0H 0.
e Hvr..0 N
\ Ni \N N ---;"-\

Cl 1-86 Cl [0413] Synthesis of 2-(2-04-0(7-chloroimidazo[1,5-alpyridin-1-y1)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-alpyridin-8-y1)acetic acid (1-86). To a solution of methyl 2-(2444(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)acetate (50 mg, 0.096 mmol) in Et0H (3 mL) was added NaOH (3 mL, 1 M solution in H20).
The resulting reaction was stirred at RT for 1 h. HC1 (1 M, 3 mL) was added and the reaction was concentrated to give a crude product, which was purified by prep-HPLC to give 2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetic acid (16.6 mg, 35% yield) as a white solid. ESI-MS [M+H]+: 504.1. Purity: 97.1%. 1E1 NMR (400 MHz, DMS0): 6 8.64 (t, J = 5.6 Hz, 1H), 8.30-8.28 (m, 2H), 8.23 (s, 1H), 8.10 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.61 (s, 1H), 6.84 (s, 1H), 6.63 (dd, J = 7.4, 2.0 Hz, 1H), 5.38 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 3.51 (s, 2H), 1.87-1.81 (m, 1H), 0.89-0.83 (m, 2H), 0.62-0.56 (m, 2H).
Example 87 Scheme 87 LiBH4 NJ \ ____________________________________ v.
N -----\ THF/Me0H

CI
CI
209 [0414] Synthesis of N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-46-cyclopropyl-8-(hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (1-87). To the solution of methyl 2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate (20 mg, 0.039 mmol) in THF/Me0H (3 mL/1 mL) was added LiBH4 (4.25 mg, 0.195 mmol).
The resulting reaction was stirred at RT for 1 h. The reaction was quenched with H20 (3 mL) and concentrated in vacuo to give the crude, which was purified with prep-HPLC
to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(hydroxyethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (7.1 mg, 37% yield) as a white solid. ESI-MS [M+H]+: 490.2. Purity: 99.6%. 1H NMR (400 MHz, DMS0): 6 8.58 (t, J = 5.7 Hz, 1H), 8.34-8.28 (m, 2H), 8.20-8.12 (m, 2H), 7.87 (s, 1H), 7.79-7.73 (m, 1H), 7.65 (s, 1H), 6.84 (s, 1H), 6.65 (dd, J = 7.5, 2.1 Hz, 1H), 5.39 (s, 2H), 4.78 (t, J = 5.8 Hz, 1H), 4.55 (d, J = 5.8 Hz, 2H), 3.74-3.70 (m, 2H), 2.96 (t, J = 6.7 Hz, 2H), 1.91-1.85 (m, 1H), 0.92-0.79 (m, 2H), 0.67-0.63 (m, 2H).
Example 88 [0415] See Example 89 for Synthesis of 1-((5-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (1-88).
vcrN
\N N

CI
210 Example 89 Scheme 88 12, K2co3, A
rt, 2 h k >-13(OH)2 n .2N, NH 0 H2N N NH2 Pd(0A02, SPhos, K3PO4, H2N N NH2 toluene/H20, 100C, 9 h ciJLci N

NIN) -N Cl ci and DMF, 90 C, 16h NH2 1NJ h CsCO3, DMF, rt \N
NH2 43,11y1õ....)....,,Q\ and [0416] Synthesis of 3-iodopyridine-2,6-diamine. To a solution of 3-iodopyridine-2,6-diamine (5.0 g, 45.9 mmol) in 2-methyltetrahydrofuran (35 mL) was added K2CO3 (6.7 g, 48.2 mmol) followed by addtion of a solution of I2 (12.2 g, 48.2 mmol) in 2-methyltetrahydrofuran (20 mL) dropwise over 0.5 h. The resulting reaction was stirred at RT for 5 h.
Water (100 mL) was added to the reaction and extracted with Et0Ac (150 mL x 2). The combined organic layers were concentrated in vacuo to give the crude, which was purified by silica gel chromatography (DCM/Me0H = 20/1) to give 3-iodopyridine-2,6-diamine (8.5 g, yield: 78.7%) as a yellow solid.
ESI-MS [M+H]: 236Ø
[0417] Synthesis of 3-cyclopropylpyridine-2,6-diamine. To a solution of 3-iodopyridine-2,6-diamine (2.0 g, 8.5 mmol) and cyclopropylboronic acid (2.2 g, 25.5 mmol) in toluene/H20 (30 mL/3 mL) was added K3PO4 (6.3 g, 29.8 mmol), SPhos (1.0 g, 2.6 mmol) and Pd(OAc)2 (0.3 g, 1.3 mmol). The resulting mixture was stirred at 90 C for 16 h under N2 atmosphere. Water (100 mL) was added to the reaction and extracted with Et0Ac (100 mL x 3).
The combined organic layers were concentrated and purified by silica gel chromatography
211 (DCM/Me0H = 20/1) to give 3-cyclopropylpyridine-2,6-diamine (0.78 g, yield:
61.9%) as a yellow solid. ESI-MS [M+H]+: 150.3.
[0418] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo11,2-alpyridin-5-amine and 2-(chloromethyl)-8-cyclopropylimidazo[1,2-alpyridin-5-amine. To a solution of 3-cyclopropylpyridine-2,6-diamine (0.48 g, 3.22 mmol) in DNIF (10 mL) was added 1, 3-dichloropropan-2-one (2.04 g, 16.1 mmol). The mixture was stirred at 90 C for 16 h. Water (50 mL) was added to the reaction and extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated and purified by silica gel chromatography (DCM/Me0H =
20/1) to give mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-5-amine and 2-(chloromethyl)-8-cyclopropylimidazo[1,2-a]pyridin-5-amine (0.18 g, yield:
16.4%) as a yellow solid. ESI-MS [M+H]+: 222.3.
[0419] Synthesis of 1-((5-amino-6-cyclopropylimidazo11,2-alpyridin-2-yl)methyl)-N-((7-chloroimidazo11,5-alpyridin-1-yHmethyl)-1H-pyrazole-4-carboxamide (1-88) and 1-((5-amino-8-cyclopropylimidazo[1,2-a]pyridin-2-yHmethyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yHmethyl)-1H-pyrazole-4-carboxamide (1-89). To a mixture of 2-(chloromethyl)-cyclopropylimidazo[1,2-a]pyridin-5-amine and 2-(chloromethyl)-8-cyclopropylimidazo[1,2-a]pyridin-5-amine (80 mg, 0.36 mmol) and N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (99 mg, 0.36 mmol) in DMF (4 mL) was added Cs2CO3 (234 mg, 0.72 mmol). The mixture was stirred at RT for 8 h. Water (50 mL) was added to the reaction and extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated and purified by prep-HPLC to give 145-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (16.4 mg, yield: 10.0%) as a white solid. ESI-MS [M+H]+: 461.2. Purity: 99.5% and 145-amino-8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (4.1 mg, yield: 2.5%) as a white solid. ESI-MS
[M+H]+: 461.1.
Purity: 95.3%. 145-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide 1HNMR (400 MHz, DMS0): 6 8.58 (t, J = 5.6 Hz, 1H), 8.37-8.13 (m, 3H), 7.82 (d, J = 31.9 Hz, 3H), 6.92 (d, J = 9.0 Hz, 1H), 6.74-6.58 (m, 2H), 6.41 (s, 2H), 5.36 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 1.76 (m, 1H), 0.88 (m, 2H), 0.51 (t, J = 4.7 Hz, 2H). 145-amino-8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide. 1E1
212 NMR (400 MHz, DMS0): 6 8.60 (t, J = 5.7 Hz, 1H), 8.30 (d, J = 7.1 Hz, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 6.84-6.59 (m, 2H), 6.28 (s, 2H), 5.85 (d, J = 7.6 Hz, 1H), 5.42 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 2.23 (m, 1H), 0.92-0.79 (m, 2H), 0.72 (m, 1H).
Example 90 Scheme 89 D

CI HCI
OH
HATU, DIPEA, DMF
rt, 12 h 0 Cl [0420] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl-d2)-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-90). To a solution of 1((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (65 mg, 0.23 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methan-d2-amine hydrochloride (50 mg, 0.23 mmol) and HATU (114 mg, 0.3 mmol) in DMF (15 mL) was added DIPEA (148 mg, 1.15 mmol). The resulting reaction was stirred at RT for 12 h. H20 (25 mL) was added to the reaction and extracted with Et0Ac (25 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated to give the crude, which was purified with prep-TLC
(DCM/Me0H = 10/1) to give the N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl-d2)-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (20 mg, yield:
19%). ESI-MS [M+H]+: 448.2. Purity: 95.1%. 1H NMR (400 MHz, DMS0): 6 8.56 (s, 1H), 8.32-8.29 (m, 3H), 8.20 (s, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 6.99 (d, J = 9.3 Hz, 1H), 6.71-6.58 (m, 1H), 5.38 (s, 2H), 1.91 (ddd, J =
13.3, 8.6, 5.1 Hz, 1H), 0.91 (q, J = 5.7 Hz, 2H), 0.66 (q, J = 5.0 Hz, 2H).
213 Example 91 Scheme 90 N NO

0 Cl NN
I , NH2 DMF, 90 C, 3 h ---N Cs2CO3, DMF, 50 C, 2 h CI
[0421] Synthesis of methyl 2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate.
The mixture of methyl 6-aminonicotinate (1.20 g, 7.88 mmol) and 1,3-dichloropropan-2-one (2.0 g, 15.77 mmol) in DMF (10 mL) was heated to 90 C and stirred for 3 h. The reaction mixture was poured into H20 (60 mL), adjusted pH to 9 by addition of aqueous NaHCO3 and extracted with Et0Ac (60 mL x 3). The combined organics were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated and purified by column chromatography (Et0Ac/PE
= 1:1) to afford methyl 2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate (570 mg, 32%) as a yellow solid. ESI-MS [M+H]+: 225.1.
[0422] Synthesis of methyl 2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylate (I-91).
A mixture of N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (100 mg, 0.36 mmol), methyl 2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate (90 mg, 0.40 mmol) and Cs2CO3 (235 mg, 0.72 mmol) in DNIF (5 mL) was stirred for 2 h at 50 C. The reaction mixture was poured into H20 (50 mL), solid was precipitated and filtered to give the crude product, which was purified by column chromatography (DCM:Me0H = 10:1) to afford methyl 24(44(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylate (70 mg, 42%) as a yellow solid.
ESI-MS
[M+H]+: 464.1. Purity: 99.39%. 111 NMR (400 MHz, DMS0): 6 9.32 (s, 1H), 8.59(t, J = 5.5 Hz, 1H), 8.29 (m, 3H), 8.01 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.60 (dd, J =
25.5, 9.5 Hz, 2H), 6.65 (dd, J = 7.5, 1.8 Hz, 1H), 5.46 (s, 2H), 4.56 (d, J = 5.6 Hz, 2H), 3.87 (s, 3H).
214 Example 92 Scheme 91 H2N CI .).C1 H2N CN
\OH
CI N, ____________________________ 111.
N
Pd(OAc)2, SPhos Et0H, 85 C, 16 h Br K3PO4, toluene/H20 refluxed, 16 h CI

N/ N

H
HN
CN
H
v_LCI---;N
/
N NJ
Cs2CO3, DMF, 16 h \

[0423] Synthesis of 2-amino-5-cyclopropylnicotinonitrile. To a mixture of 2-amino-5-bromonicotinonitrile (1 g, 5.1 mmol), cyclopropylboronic acid (647 mg, 7.6 mmol) and K3PO4 (3.78 g, 17.85 mmol) in toluene/H20 (20 mL/2 mL) was added Pd(OAc)2 (114 mg, 0.51 mmol) and SPhos (209 mg, 0.51 mmol). The mixture was stirred at 95 C for 16 h. The reaction was cooled to RT and the reaction residue was filtered. The filtrate was concentrated to give the crude product which was purified by silica gel chromatography (EA/PE = 4/1) to give 2-amino-5-cyclopropylnicotinonitrile (570 mg, yield: 71%) as a yellow solid. ESI-MS
[M+H]: 160.1.
[0424] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo 11,2-al pyridine-carbonitrile. To a solution of 2-amino-5-cyclopropylnicotinonitrile (570 mg, 3.58 mmol) in Et0H (20 mL) was added 1, 3-dichloropropan-2-one (1.37 g, 10.75 mmol). The reaction mixture was stirred at 85 C for 16 h. The reaction was concentrated and the residue was diluted with NaHCO3 (aq, 20 mL) and extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated to give the crude which was purified by silica gel chromatography (EA/PE = 2/1) to give 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (500 mg, yield: 58%) as a yellow solid. ESI-MS [M+H]: 232.1.
215 [0425] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-92). To a mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (80 mg, 0.35 mmol) in dry DMF (5 mL) was added N-((7-chloroimidazo[1,5-a]pyridin-l-yl)methyl)-1H-pyrazole-4-carboxamide (95 mg, 0.35 mmol) and Cs2CO3 (338 mg, 1.04 mmol). The mixture was stirred at RT for 16 h. Then H20 (30 mL) was added to the reaction and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude, which was purified by prep-TLC
(DCM/Me0H =
10/1) to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (34.5 mg, yield:
21%) as a white solid. ESI-MS [M+H]+: 471.1. Purity: 98.67%. 111NMR (400 MHz, DMS0): 6 8.67 (d, J = 1.5 Hz, 1H), 8.60 (t, J = 5.7 Hz, 1H), 8.31-8.29 (m, 2H), 8.24 (s, 1H), 7.87 (d, J =
13.6 Hz, 2H), 7.78 (t, J = 1.9 Hz, 2H), 6.65 (dd, J = 7.4, 2.1 Hz, 1H), 5.47 (s, 2H), 4.56 (d, J =
5.7 Hz, 2H), 1.99-1.95 (m, 1H), 0.97-0.93 (m, 2H), 0.77-0.73 (m, 2H).
Example 93 Scheme 92 N%\ vL
SOC12, Et0H õ..._ õõ)......,q N

CI

HO -4--0 ..---N

[0426] Synthesis of ethyl 3-(4-(((7-chloroimidazo11,5-alpyridin-1-y1)methyl)carbamoy1)-1-((6-cyclopropylimidazo11,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-y1)propanoate (1-93). To a solution of 3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-y1)propanoic acid (20 mg, 0.04 mmol) in Et0H (4 mL) was added SOC12 (0.5 mL).
The reaction was stirred at RT for 2 h. After concentration, the crude product was purification by prep-TLC
(DCM/Me0H = 10/1) to give ethyl 3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-y1)propanoate (13 mg, yield: 57%) as a white solid. ESI-MS [M+H]: 546.2.
Purity: 89.6%. 111
216 NMR (400 MHz, Me0D): 6 8.23 (s, 1H), 8.17-8.11 (m, 2H), 8.01 (d, J = 3.3 Hz, 1H), 7.71 (d, J
= 0.8 Hz, 1H), 7.66 (s, 1H), 7.35 (d, J = 9.4 Hz, 1H), 7.07 (dd, J = 9.4, 1.7 Hz, 1H), 6.60 (dd, J =
7.5, 2.0 Hz, 1H), 5.33 (s, 2H), 4.65 (s, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.15 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 1.95-1.89 (m, 1H), 1.14 (t, J = 7.1 Hz, 3H), 1.01-0.90 (m, 2H), 0.72-0.66 (m, 2H).
Example 94 Scheme 93 TFA
Cl ClNT
1010 HATU, DIPEA, 1\01c4 DMF, rt, 16 h [0427] Synthesis of N-(2-(7-chloroimidazo [1,5-a]pyridin-1-yl)ethyl)-1-((6-cyclopropylimidazo [1,2-a] pyridin-2-yHmethyl)-1H-pyrazole-4-carboxamide (1-94). A
mixture of 1((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (60 mg, 0.2 mmol), 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)ethanamine (60 mg, 0.2 mmol), HATU (90 mg, 0.24 mmol) and DIPEA (0.1 mL, 0.5 mmol) in DMF (10 mL) was stirred at RT
for 16 h. H20 (20 mL) was added to reaction and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified by prep-HPLC to give N-(2-(7-chloroimidazo[1,5-a]pyridin-1-yl)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (31 mg, yield: 33.8%) as a yellow solid. ESI-MS [M+H]: 460.1.
Purity: 100.0%.
1H NMR (400 MHz, DMS0): 6 8.34 (s, 1H), 8.29 (s, 1H), 8.26 (d, J = 7.4 Hz, 1H), 8.14 (s, 2H), 7.76 (d, J = 22.4 Hz, 2H), 7.60 (d, J = 0.9 Hz, 1H), 7.40 (d, J = 9.4 Hz, 1H), 7.00 (dd, J = 9.4, 1.7 Hz, 1H), 6.57 (dd, J = 7.5, 2.0 Hz, 1H), 5.39 (s, 2H), 3.44 (dd, J = 13.2, 6.9 Hz, 3H), 2.95 (t, J =
7.2 Hz, 2H), 2.01-1.77 (m, 1H), 1.00-0.76 (m, 2H), 0.75-0.54 (m, 2H).
217 Example 95 Scheme 94 io HN CS2CO3 \N N \
N
F DMF, rt, 2 h LiOH)1.
0 THF/Et0H/H20, 80 C, 3 h 0 F F F F
NH2 .vCr_. _N\
Br HATU,DIEA 1-95 ________ 111. 0 DMF, rt, 2 h F F Br [0428] Synthesis of ethyl 1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylate. A solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine (40 mg, 0.19 mmol), N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (60 mg, 0.19 mmol), and Cs2CO3 (248 mg, 0.76 mmol) in DMF (3 mL) was stirred at RT for 2 h. Then the reaction mixture was diluted with H20 (40 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated to give the desired compound ethyl 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylate (400 mg, yield: 67%) as brown oil, which was used in the next step without purification. ESI-MS
[M+H]+: 361.1.
[0429] Synthesis of 1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylic. A solution of ethyl 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylate (400 mg, 1.11 mmol) and LiOH (233 mg, 5.55 mmol) in THF/Et0H/H20 (10 mL/10 mL/5 mL) was stirred at RT
for 3 h.
Most of the solvent was concentrated and the pH of the residue was adjusted to 4 by adding 1 M
HC1 solution. Solid was precipitated and filtered to give 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (300 mg, yield:
81%) as a brown solid, which was used in the next step without purification. ESI-MS [M+H]+:
333.1.
[0430] Synthesis of N-((7-bromoimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-al pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-
218 carboxamide (1-95). A solution of 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (65 mg, 0.19 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (50 mg, 0.19 mmol), HATU (149 mg, 0.39 mmol) and DIPEA (76 mg, 0.58 mmol) in DMF (5 mL) was stirred at RT for 2 h. Then the reaction mixture was diluted with H20 (25 mL) and extracted with Et0Ac (25 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified by column chromatography (PE/EA = 10/1) to give the desired compound N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxamide (18 mg, yield: 18%) as a white solid. ESI-MS [M+H]+: 540.1. Purity: 98.48%. IIINNIR (400 MHz, DMS0): 6 8.77 (s, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.39 (s, 1H), 8.26 (d, J = 7.4 Hz, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.38 (t, J = 53.8 Hz, 2H), 6.83-6.76 (m, 1H), 5.69 (s, 2H), 4.59 (s, 2H), 2.11-2.02 (m, 1H), 1.07-0.98 (m, 2H), 0.82-0.72 (m, 2H).
Example 96 Scheme 95 xo-kcj., HO--1 Li0H, Me0H, THF

NI H Hp, 40 C, 1 h H

CI
CI
[0431] Synthesis of 2-44-(((7-chloroimidazo[1,5-alpyridin-1-y1)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)imidazo[1,2-alpyridine-6-carboxylic acid (1-96). To a solution of methyl 24(44(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylate (35 mg, 0.075 mmol) in methanol (2 mL), THF
(2 mL) and H20 (1 mL) was added lithium hydroxide monohydrate (44 mg, 1.05 mmol). The mixture was stirred for 1 h at 40 C. The pH value of the residue was adjusted to 4 by adding 1 M HC1 solution. The resulting mixture was concentrated and purified by prep-HPLC to give 2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-
219 lyl)methyl)imidazo[1,2-a]pyridine-6-carboxylic acid (25 mg, 74%) as a white solid. ESI-MS
[M+H]+: 225.1. Purity: 93.06%. IIINMR (400 MHz, DMS0): 6 13.15 (s, 1H), 9.25 (s, 1H), 8.59 (t, J = 5.8 Hz, 1H), 8.31 (m, 2H), 8.25 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.79 (s, 1H), 7.59 (m, 2H), 6.65 (dd, J = 7.5, 2.0 Hz, 1H), 5.45 (s, 2H), 4.56 (d, J = 5.7 Hz, 2H).
Example 97 Scheme 96 \ NJ \
\ )\T
1431r0H 1\131Li HATU, DIEA, DMF, rt, 12 h 1-97 [0432] Synthesis of N-((7-bromo-8-fluoroimidazo11,5-alpyridin-1-y1)methyl)-1-((6-cyclopropy limidazo[1,2-alpyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (1-97). To a solution of 1((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (60 mg, 0.21 mmol), (7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (84 mg, 0.32 mmol) and HATU (120 mg, 0.31 mmol) in DMF (5 mL) was added DIPEA
(81 mg, 0.63 mmol). The resulting reaction was stirred at RT for 12 h. H20 (25 mL) was added to the reaction, extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with prep-TLC (DCM/Me0H = 10/1) to the N47-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (20 mg, yield: 19%) as a white solid. ESI-MS [M+H]+: 508.1. Purity: 98.9%. 11-1NWIR (400 MHz, DMS0): 6 8.46 (d, J = 2.2 Hz, 1H), 8.42 (t, J = 4.8 Hz, 1H), 8.33 (s, 1H), 8.20 (s, 1H), 8.14 (d, J = 7.3 Hz, 1H), 7.84 (s, 1H), 7.72 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 6.99 (d, J = 9.3 Hz, 1H), 6.82 (t, J = 6.6 Hz, 1H), 5.39 (s, 2H), 4.62 (d, J = 5.2 Hz, 2H), 1.94-1.88 (m, 1H), 0.95-0.87 (m, 2H), 0.71-0.61 (m, 2H).
220 Example 98 Scheme 97 rN
N
N N=-1\
NY-kOH
1\1\13(1111 ___________ ;NI __________________ Jo HATU, DIPEA, 8 0 I-9 DMF,rt, 18 h [0433]
Synthesis of 1-((6-cyclopropylimidazo[1,2-131pyridazin-2-y1)methyl)-N-((7-ethynylimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1-98). A
solution of 1((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (66 mg, 0.23 mmol), (7-ethynylimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (47 mg, 0.23 mmol), HATU (175 mg, 0.46 mmol) and DIPEA (89 mg, 0.69 mmol) in DMF (5 mL) was stirred at RT for 2 h. Then the reaction mixture was diluted with H20 (30 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude, which was purified by prep-HPLC to give 14(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-N47-ethynylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (10 mg, yield: 10%) as a white solid. ESI-MS [M+H]+:
437.2. Purity: 97.51%. 111 NMR (400 MHz, DMS0): 6 8.61 (t, J = 5.6 Hz, 1H), 8.48 (s, 1H), 8.27 (d, J = 7.1 Hz, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.96-7.91 (m, 2H), 7.85 (s, 1H), 7.11 (t, J =
7.7 Hz, 1H), 6.63 (d, J = 7.3 Hz, 1H), 5.42 (s, 2H), 4.60 (d, J = 5.7 Hz, 2H), 4.30 (s, 1H), 2.22-2.13 (m, 1H), 1.10-1.03 (m, 2H), 1.00-0.94 (m, 2H).
221 Example 99 Scheme 98 ICI,vorN
HNO ______ õCrN\

Li0H, THF/Et0H/H20, 80 C 3 h 1\1213,1(0,,/
42.1,0H
F CS2CO3, DMF, rt, 2 h 11)/
N = , N
,N
HATU,DIEA
F F 1-99 Cl DMF, rt, 2 h [0434] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylate. A mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine (40 mg, 0.19 mmol), N47-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (60 mg, 0.19 mmol) and Cs2CO3 (248 mg, 0.76 mmol) in DMF (2 mL) was stirred at RT for 2 h. Then the reaction mixture was diluted with H20 (40 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the desired compound ethyl 14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylate (400 mg, yield: 67%) as brown oil, which was used in the next step without purification. ESI-MS
[M+H]+: 361.1.
[0435] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylic. A solution of ethyl 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylate (400 mg, 1.11 mmol) and LiOH (233 mg, 5.55 mmol) in THF/Et0H/H20 (10 mL/10 mL/5 mL) was stirred at RT
for 3 h.
Most of the solvent was concentrated and the pH of the residue was adjusted to 4 by adding 1 M
HC1 solution. Solid was precipitated and filtered to give the desired compound 14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (300 mg, yield: 81%) as a brown solid, which was used in the next step without purification.
ESI-MS [M+H]: 333.2.
222 [0436] Synthesis of N4(7-chloroimidazo[1,5-alpyridin-1-y1)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxamide (1-99). A solution of 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (65 mg, 0.19 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (41 mg, 0.19 mmol), HATU (149 mg, 0.39 mmol) and DIPEA (76 mg, 0.58 mmol) in DIVIF (5 mL) was stirred at RT for 2 h. Then the reaction mixture was diluted with H20 (30 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude, which was purified by column chromatography (DCM/Me0H = 10/1) to give the desired compound N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1, 2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxamide (18 mg, yield: 18%) as a white solid. ESI-MS [M+H]+: 496.2. Purity: 91.43%. 1H NMR (400 MHz, DMS0): 6 8.61 (t, J =
5.6 Hz, 1H), 8.48 (s, 1H), 8.27 (d, J = 7.1 Hz, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.96-7.91 (m, 2H), 7.85 (s, 1H), 7.11 (t, J = 7.7 Hz, 1H), 6.63 (d, J = 7.3 Hz, 1H), 5.42 (s, 2H), 4.60 (d, J = 5.7 Hz, 2H), 4.30 (s, 1H), 2.22-2.13 (m, 1H), 1.10-1.03 (m, 2H), 1.00-0.94 (m, 2H).
223 Example 100 Scheme 99 HO HI,\1.3.....114 ...õ- ......N /CI
v...6- \

Cs2CO3, DMF, NI":\
Nralig........ ...).....,N IBX, DIAS
40 C, 4 h CI

,C) 6.....N
",.. N---i¨\N
,vi..._ N\ Ph 0 Ph THF, 25 C, 6 h õN....,"
Nal.fy.....)........._ N......cl_.

CI
I-100a CI
=,......õ,07,.....i H07.0 r NaBH NI 4, CuCI, Me0H - Li0H, THF, Et0H
25 C, 16 h N--.1 \N N":" \ 25 C, 16 h õ N--_, \x, N ---"'N
43.....1,g .........}...\ 4-õ,...),..11,Li ...._.,,,I \

CI
CI
I-100b I-100c [0437] Synthesis of N4(7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo 11,2-alpyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. To a mixture of (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (370 mg, 1.56 mmol) in dry DMF (10 mL) was added N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (430 mg, 1.56 mmol) and Cs2CO3 (1.53 g, 4.68 mmol). The mixture was stirred at 25 C for 16 h. Then H20 (50 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude, which was purified by silica gel chromatography (DCM/Me0H = 10/1) to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (400 mg, yield: 53.8%) as a yellow solid. ESI-MS [M+H]+: 476.2.
224 [0438] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropyl-8-formylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide. To a mixture of N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (400 mg, 0.84 mmol) in DMSO (10 mL) was added 2-iodoxybenzoic acid (472 mg, 1.68 mmol). The mixture was stirred at 40 C for 4 h. Then H20 (80 mL) was added, and the precipitate was filtered and dired to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (200 mg, yield: 50%) as a white solid, which was used in the next step without purification. ESI-MS
[M+H]+: 474.1.
[0439] Synthesis of ethyl 3-(24(4-(((7-chloroimidazo11,5-alpyridin-1-y1)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo11,2-alpyridin-8-y1)acrylate (I-100a). To a mixture of N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (200 mg, 0.4 mmol) in dry THF (8 mL) was added Ethyl (triphenylphosphoranylidene)acetate (152 mg, 0.44 mmol) at 0 C. The mixture was stirred at 25 C for 6 h, concentrated to give the crude, which was purified by Pre-TLC (DCM/Me0H = 10/1) to give ethyl 3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acrylate (120 mg, yield: 52%) as a yellow solid. ESI-MS
[M+H]+: 544.2. purity: 93.12%.
1H NMR (400 MHz, DMSO) 6 8.59 (t, J = 5.7 Hz, 1H), 8.43-8.42 (m, 1H), 8.31-8.29 (m, 2H), 8.22 (s, 1H), 7.90 (s, 1H), 7.79-7.75 (m, 3H), 7.64-7.60 (m, 1H), 7.44-7.43 (m, 1H), 6.64 (dd, J =
7.4, 2.1 Hz, 1H), 5.47 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 1.95-1.91 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H), 0.94-0.91 (m, 2H), 0.76-0.72 (m, 2H).
[0440] Synthesis of ethyl 3-(24(4-(((7-chloroimidazo11,5-alpyridin-1-y1)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo11,2-alpyridin-8-y1)propanoate (I-100b). To a mixture of ethyl 3-(2444(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)acrylate (120 mg, 0.22 mmol) in Me0H (5 mL) was CuCl (43 mg, 0.44 mmol) and NaBH4 (25 mg, 0.66 mmol). The mixture was stirred at 25 C for 16 h. Water (30 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried
225 over Na2SO4, filtered and concentrated to give the crude, which was purified by prep-TLC
(DCM/Me0H = 10/1) to give ethyl 3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (110 mg, yield: 91%) as a yellow solid. ESI-MS [M+H]+: 546.2.
Purity: 99.11%.
1H NMR (400 MHz, DMS0): 6 8.59 (t, J = 5.5 Hz, 1H), 8.31-8.29 (m, 2H), 8.20-8.19 (m, 2H), 7.88 (s, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 6.82 (s, 1H), 6.64 (dd, J = 7.4, 2.0 Hz, 1H), 5.40 (s, 2H), 4.55 (d, J = 5.6 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 7.6 Hz, 2H), 1.90-1.84 (m, 1H), 1.14 (t, J = 7.1 Hz, 3H), 0.92-0.87 (m, 2H), 0.66-0.62 (m, 2H).
[0441] Synthesis of 3-(2-04-0(7-chloroimidazo[1,5-a1pyridin-1-y1)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-alpyridin-8-y1)propanoic acid (I-100c). To a mixture of ethyl 3-(24(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (40 mg, 0.07 mmol) in THF/Et0H/H20 (1 mL/1 mL/1 mL) was added LiOH (5.3 mg, 0.22 mmol). The mixture was stirred at 25 C for 6 h. The pH of the residue was adjusted to 4 by adding 1 M HC1 solution. The mixture was concentrated and purified by prep-HPLC to give 3-(24(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (14 mg, yield: 37%) as a yellow solid.
ESI-MS [M+H]: 518.2. Purity: 99.18%. 1H NMR (400 MHz, DMSO) 6 12.18 (s, 1H), 8.59 (t, J
= 5.6 Hz, 1H), 8.31-8.29 (m, 2H), 8.20-8.18 (m, 2H), 7.88 (s, 1H), 7.78 (s, 1H), 7.65 (s, 1H), 6.82 (s, 1H), 6.66-6.63 (m, 1H), 5.40 (s, 2H), 4.55 (d, J = 5.6 Hz, 2H), 3.04 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 1.89-1.85 (m, 1H), 0.90-0.88 (m, 2H), 0.66-0.64 (m, 2H).
226 Example 101 Scheme 100 N':::\N
HNN)....11-\11 -..,,),_-.-.\ HO
HO T\L \
¨

.,.., N CI ___________________________ \N N%-:\ SOCl2, THF
).-1 Cs2CO3, DMF, NO..; --... N \
25 C, 3 h 25 C, 16 h CI
v.:1...a...r. r0 I\k) .,..= ____N 0 1.õ,,...õNH Cs2CO3DMF, 6 v.,...,..-_N
===,õ N....) , Cl [0442] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-46-cyclopropyl-8-(hydroxymethyl)imidazo 11,2-alpyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. To a mixture of (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (370 mg, 1.56 mmol) in dry DMF (10 mL) was added N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (430 mg, 1.56 mmol) and Cs2CO3 (1.53 g, 4.68 mmol). The mixture was stirred at 25 C for 16 h. Then H20 (100 mL) was added to the reaction and extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude, which was purified by prep-TLC (DCM/Me0H = 10/1) to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (400 mg, yield: 53.9%) as a yellow solid. ESI-MS [M+H]+: 476.1.
[0443] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-48-(chloromethyl)-6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide. To a mixture of N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide
227 (50 mg, 0.1 mmol) in THF (2 mL) was added SOC12 (0.5 mL). The mixture was stirred at 25 C
for 3 h. Then the reaction mixture was concentrated to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (50 mg, yield: 96%) as a yellow solid, which was used into the next step without purification. ESI-MS [M+H]+: 494.1.
[0444] Synthesis of N-((7-chloroimidazo11,5-a1pyridin-1-yl)methyl)-1-46-cyclopropyl-8-(morpholinomethyl) imidazo[1,2-alpyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-101). To a mixture of N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (50 mg, 0.1 mmol) in dry DMF (3 mL) was added morpholine (17.6 mg, 0.2 mmol) and Cs2CO3 (163 mg, 0.5 mmol). The mixture was stirred at 25 C for 16 h. Water (30 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude, which was purified by prep-TLC
(DCM/Me0H = 8/1) to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(morpholinomethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (11.6 mg, yield: 21%) as a white solid. ESI-MS [M+H]+: 545.2. Purity: 99.15%. lEINIVIR
(400 MHz, DMS0): 6 8.58 (t, J = 5.7 Hz, 1H), 8.31-8.29 (m, 2H), 8.22-8.19 (m, 2H), 7.87 (s, 1H), 7.77 (m, 1H), 7.68 (s, 1H), 6.99 (s, 1H), 6.64 (dd, J = 7.5, 2.1 Hz, 1H), 5.39 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 3.75 (s, 2H), 3.60-3.58 (m, 4H), 2.44 (s, 4H), 1.96-1.89 (m, 1H), 0.94-0.89 (m, 2H), 0.66-0.62 (m, 2H).
228 Example 102 Scheme 101 0 SEM, 0¨/
H7.....r OJ SEM, 11J1 N'N I 0 SEMCI, NaH. 1HP SEM ,N 0 III .. NaH. CH31. CS2, 1HE

BuLA, 1HP, -78 C
Br 0 Bu3SnH, AIBN Nr TBAF, IHI, N1-1 3.-90 .11----...--PhMe, 120 C
Cs2CO3, DMI, Isr-N
LAOH. 1HE Et0H, H20, 50 C H2N
______________ I"' I\IN\ \ OH ___________________ rpm,yq ..
HATU, DIPEA, DMI, 1-102 CI

[0445] Synthesis of ethyl 3-bromo-14(2-(trimethylsilyl)ethoxy)methyl)-111-pyrazole-4-carboxylate. To a solution of ethyl 3-bromo-1H-pyrazole-4-carboxylate (547 mg, 2.5 mmol) and NaH (150 mg, 3.75 mmol, 60% oil) in THF (5 mL) and under N2 was added SEMC1 (458 mg, 2.75 mmol) at 0 C. The reaction mixture was stirred at RT for 2 h. The reaction was quenched with H20 (30 mL) and extracted with Et0Ac (30 mL x 2).
The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford ethyl 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate as a yellow oil (873 mg, yield: 99%) and a mixture of N1 and N2 regioisomers. ESI-MS [M+H]+:
350.1.
[0446] Synthesis of ethyl 3-(3-hydroxyoxetan-3-y1)-14(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate. To a solution of ethyl 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (615 mg, 1.76 mmol) in THF (8 mL) under N2 was added BuLi (0.9 mL, 2.11 mmol, 2.4 M solution in hexane) at -78 C. Then oxetan-3-one (2.1 mL, 35.2 mmol) was added. The reaction was allowed to warm to RT and stirred for 2 h. The reaction mixture was quenched with saturated NH4C1 solution (20 mL) and extracted with Et0Ac (50 mL x3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude, which was purified by a column flash
229 (PE :EA = 2:1) to get ethyl 3-(3-hydroxyoxetan-3-y1)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (169 mg, yield: 28%) as a yellow oil. ESI-MS [M+H]+:
343.2.
[0447] Synthesis of ethyl 3-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-y1)-1-02-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate. To a mixture of NaH
(54 mg, 1.34 mmol, 60% oil) in THF (1 mL) was added a solution of ethyl 3-(3-hydroxyoxetan-3-y1)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (306 mg, 0.89 mmol) in THF (0.5 mL) at 0 C dropwise. The resulting solution was stirred at 0 C for 30 min.
Then a solution of CS2 (102 mg, 1.34 mmol) in THF (0.5 mL) was added to the reaction at 0 C
dropwise. The resulting solution was stirred at 0 C for another 1 h. To the mixture above was added a solution of iodomethane (190 mg, 1.34 mmol) in THF (0.5 mL) dropwise at 0 C. The resulting solution was stirred at 0 C for 1 h, then quenched with aqueous NH4C1 (10 mL), and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford ethyl 3-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-y1)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (385 mg crude) as yellow oil, which was used into next step without further purification. ESI-MS [M+H]+:
433.1.
[0448] Synthesis of ethyl 3-(oxetan-3-y1)-14(2-(trimethylsilyl)ethoxy)methyl)- 111-pyrazole -4-carboxylate. To a solution of ethyl 3-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-y1)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (385 crude from previous step) in toluene (10 mL) were added Bu3SnH (311 mg, 1.07 mmol) and AIBN (29 mg, 0.18 mmol). The resulting mixture was stirred at 120 C for 3 h. The reaction was cooled to RT and concentrate in vacuo to give the crude, which was purified by silica gel column (PE/EA = 5/1) to isolate ethyl 3-(oxetan-3-y1)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (204 mg, yield: 70%) as yellow oil. ESI-MS [M+H]+: 327.2.
[0449] Synthesis of ethyl 3-(oxetan-3-y1)-1H-pyrazole-4-carboxylate. To a solution of TBAF (3.2 mL, 3.13 mmol, 1 M solution in THF) was added ethyl 3-(oxetan-3-y1)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (204 mg, 0.63 mmol).
The mixture was stirred at 90 C for 8 h. H20 (25 mL) was added tothe reaction and extrated with Et0Ac (35 mL x 3). The combined organic layer were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column (PE/EA =
1/2) to isolate
230 ethyl 3-(oxetan-3-y1)-1H-pyrazole-4-carboxylate (81 mg, yield: 66%) as a white solid. ESI-MS
[M+H]+: 197.2.
[0450] Synthesis of ethyl 1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-3-(oxetan-3-y1)-1H-pyrazole-4-carboxylate. To a solution of ethyl 3-(oxetan-3-y1)-1H-pyrazole-4-carboxylate (50 mg, 0.25 mmol) in DMF (5 mL) was added 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (63 mg, 0.31 mmol) and Cs2CO3 (245 mg, 0.75 mmol). The mixture was stirred at RT for 3 h. Water (20 mL) was added and extracted with Et0Ac (30 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by silica gel column (DCM/Me0H =
20/1) to give ethyl 1-((6-cyclopropylimidazo [1,2-a]pyridin-2-yl)methyl)-3-(oxetan-3-y1)-1H-pyrazole-4-carboxylate (90 mg, yield: 98%) as a white solid. ESI-MS [M+H]+: 367.2.
[0451] Synthesis of 1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-3-(oxetan-3-y1)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(oxetan-3-y1)-1H-pyrazole-4-carboxylate (45 mg, 0.12 mmol) in THF/Et0H/H20 (2 mL/2 mL/1 mL) was added LiOH (10 mg, 0.24 mmol). The resulting mixture was stirred at 50 C for 3 h. The mixture was freeze-dried to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(oxetan-3-y1)-1H-pyrazole-4-carboxylic acid as a lithium salt (50 mg crude), which was used in the next step without purification. ESI-MS [M+H]+:
339.2.
[0452] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo11,2-a]pyridin-2-y1)methyl)-3-(oxetan-3-y1)-1H-pyrazole-4-carboxamide (I-102). To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(oxetan-3-y1)-1H-pyrazole-4-carboxylic acid (50 mg crude from previous step) in DMF (3 mL) was added (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (22 mg, 0.12 mmol), HATU (91 mg, 0.24 mmol) and DIPEA (47 mg, 0.36 mmol). The mixture was stirred at RT for 14 h.
H20 (20 mL) was added to the reaction and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give a residue. The residue was purified by flash silica gel column (DCM/Me0H = 8/1) to isolate N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-3-(oxetan-3-y1)-1H-pyrazole-4-carboxamide (34.8 mg, yield: 58%) as a white solid. ESI-MS
[M+H]+: 502.1. Purity: 97.10%. 111 NMR (400 MHz, DMS0): 6 8.43 (t, J = 5.8 Hz, 1H), 8.34 (s,
231 1H), 8.30-8.29 (m, 2H), 8.21 (s, 1H), 7.77 (s, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.00 (dd, J = 9.4, 1.7 Hz, 1H), 6.64 (dd, J = 7.5, 2.1 Hz, 1H), 5.36 (s, 2H), 4.83- 4.82 (m, J =
8.4, 2H), 4.71-4.68 (m, 2H), 4.60-4.54 (m, 1H), 4.50 (d, J = 5.7 Hz, 2H), 1.95-1.88 (m, 1H), 0.94-0.89 (m, 2H), 0.68-0.64 (m, 2H).
Example 103 Scheme 102 o sµb N Et0H
N , NaOH
N
OH NaH, THF 50 C, 3 h 60 C, 12 h CI -4¨NH2 N
N N
___________________________________ > N N
143"-{H DMF, HATU, DIEA \
rt, 3h 0) 0 0) 1-103 Cl [0453] Synthesis of ethyl 1-((8-((2-methoxyethoxy)methyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. To a mixture of ethyl 14(8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (200 mg, 0.59 mmol) in THF (10 mL) was added 2-methoxyethyl 4-methylbenzenesulfonate (1.4 g, 5.9 mmol) and NaH (25 mg, 0.88 mmol). The resulting mixture was stirred at 60 C for 12 h. Then reaction was quenched with H20 (10 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude.
The crude was purified with prep-TLC (PE/EA = 3/1) to give the ethyl 14(84(2-methoxyethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (158 mg, yield: 70%) as a white solid. ESI-MS [M+H]+: 385.1.
[0454] Synthesis of 1-((6-cyclopropy1-8-(2-methoxyethoxy)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl 146-cyclopropy1-8-(2-
232 methoxyethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (158 mg, 0.41 mmol) in Et0H (5 mL) was added NaOH (64 mg, 1.6 mmol) in H20 (2 mL). The mixture was stirred at 50 C for 3 h. The pH value of the reaction was adjusted to 2-3.
The resulting mixture was concentrated to give 1-((6-cyclopropy1-8-(2-methoxyethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (210 mg, crude) as a white solid which was used in the next step without purification. ESI-MS [M+H]: 357.1.
[0455] Synthesis of N-((7-chloroimidazo11,5-a1pyridin-1-yl)methyl)-1-46-cyclopropyl-8-(2-methoxyethoxy)imidazo11,2-a]pyridin-2-y1)methyl)-1H-pyrazole-carboxamide (I-103). To a mixture of 1-((6-cyclopropy1-8-(2-methoxyethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (210 mg, crude from last step) in DMF (5 mL) was added (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (126 mg, 0.58 mmol), DIPEA (146 mg, 1.45 mmol) and HATU (1.67 g, 0.44 mmol). The mixture was stirred at RT for 3 h. The reaction was quenched with H20 (30 mL) and was extracted with Et0Ac (30 mL
x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with prep-TLC (DCM/Me0H = 10/1) to give the N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methoxyethoxy)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (28.7 mg, yield: 13% in 2 steps) as a white solid. ESI-MS [M+H]: 534.2. Purity: 98.1%.
IIINNIR (400 MHz, DMS0): 6 8.69 (t, J = 5.6 Hz, 1H), 8.62 (s, 1H), 8.57 (s, 1H), 8.36 (d, J
= 7.5 Hz, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.64 (s, 1H), 6.77 (d, J = 7.3 Hz, 1H), 5.63 (s, 2H), 4.78 (s, 2H), 4.61 (d, J = 5.6 Hz, 2H), 3.63-3.56 (m, 2H), 3.53-3.37 (m, 2H), 3.20 (s, 3H), 2.10-2.04 (m, 1H), 1.06-1.02 (m, 2H), 0.79-0.75 (m, 2H).
Example 104 Scheme 103 OH

CH3MgBr, HF
OT, 3 h N%--\
H N
3,1c, N
I-104a I-104b CI
CI
CI
233 [0456] Synthesis of 1-((8-acety1-6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-N-((7-chloroimidazo[1,5-alpyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (I-104a). A
mixture of ethyl 2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (150 mg, 0.29 mmol) in THF (5 mL) was added CH3MgBr (1 M in THF, 1.45 mL, 1.45 mmol) at 0 C. The mixture was stirred at 0 C for 3 h under N2. The reaction was quenched with saturated NH4C1 (aq., 3 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with prep-HPLC to give 1-((8-acety1-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-chloroimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide (1.5 mg, yield: 1.05%) as a white solid. ESI-MS [M+H]+: 488.2. Purity: 95.1%. 1H NIVIR (400 MHz, Me0D): 6 8.85 (s, 1H), 8.72 (d, J = 1.0 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.34-8.30 (m, 2H), 8.06 (s, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 6.89 (dd, J = 7.5, 1.8 Hz, 1H), 5.71 (s, 2H), 4.77 (s, 2H), 2.78 (s, 3H), 2.22-2.17 (m, 1H), 1.20-1.12 (m, 2H), 1.01-0.87 (m, 2H).
[0457] From the above reaction, N4(7-chloroimidazo[1,5-a]pyridin-l-y1)methyl)-146-cyclopropyl-8-(2-hydroxypropan-2-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-104b) was also isolated (3.8 mg, yield: 2.6%) as a white solid.
ESI-MS [M+H]+:
504.2. Purity: 98.1%. 1HNMR (400 MHz, Me0D): 6 8.15 (s, 1H), 8.06-8.05 (m, 2H), 7.98 (s, 1H), 7.82 (s, 1H), 7.63 (s, 1H), 7.55 (s, 1H), 7.06 (s, 1H), 6.55-6.49 (m, 1H), 5.38 (s, 2H), 4.58 (s, 2H), 1.87-1.79 (m, 1H), 1.58 (s, 6H), 0.91-0.83 (m, 2H), 0.65-0.58 (m, 2H).
Example 105 Scheme 104 jr,õ(¨NH2 EtO0C Br EtO0C
\N HATU, DIEA, DMF N11-)31NH
rt, 3 h Br
234 [0458] Synthesis of ethyl 2-(24(4-(((7-bromo-8-fluoroimidazo11,5-a]pyridin-1-y1)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo11,2-a]pyridin-8-y1)acetate (I-105). To a mixture of 14(6-cyclopropy1-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.42 mmol) in DMF (5 mL) was added (7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (235 mg, 0.84 mmol), DIPEA (150 mg, 1.15 mmol) and HATU (240 mg, 0.63 mmol). The mixture was stirred at RT for 3 h. H20 (30 mL) was added and the reaction was extracted with Et0Ac (50 mL x 3).
The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with prep-HPLC to give the 2-(2-((4-(((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate (21.6 mg, yield: 10.2%) as a white solid. ESI-MS
[M+H]+: 494.1. Purity: 97.7%. 1HNMR (400 MHz, DMS0): 6 8.61 (s, 1H), 8.49-8.47 (m, 2H), 8.30 (s, 1H), 8.15 (d, J = 7.4 Hz, 1H), 8.08 (s, 1H), 7.96 (s, 1H), 7.56 (s, 1H), 6.84 (dd, J = 7.2, 6.2 Hz, 1H), 5.62(s, 2H), 4.64 (d, J= 5.2 Hz, 2H), 4.11-4.06 (m, 4H), 2.07-2.00(m, 1H), 1.16(t, J = 7.1 Hz, 3H), 1.06-1.01 (m, 2H), 0.77-0.73 (m, 2H).
Example 106 Scheme 105 EtO0C HOOC

,v6._ N%\
x N N
NaOH, Me0H
\
rt, 3 h ,v,i,..._-Br Br [0459] Synthesis of 2-(2-04-0(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-y1)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)acetic acid (I-106). To a solution of ethyl 2-(2-((4-(((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate (20 mg, 0.034 mmol) in Et0H (2 mL) was added NaOH (4 mg, 0.16 mmol) in H20 (1
235 mL). The mixture was stirred at RT for 3 h. The pH of the mixture was adjusted to 2-3. The resulting mixture was concentrated to give the crude, which was purified by prep-HPLC to give 2-(24(4-(((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetic acid (7.1 mg, yield:
37%) as a white solid. ESI-MS [M+H]+: 566.1. Purity: 92.9%. 1H NIVIR (400 MHz, DMS0): 6 8.48-8.38 (m, 2H), 8.36 (s, 1H), 8.20-8.18 (m, 2H), 8.14 (d, J = 7.3 Hz, 1H), 7.86 (s, 1H), 7.65 (s, 1H), 6.91 (s, 1H), 6.82 (t, J = 6.6 Hz, 1H), 5.38 (s, 2H), 4.62 (d, J = 4.9 Hz, 2H), 3.72 (s, 2H), 1.90-1.86 (m, 1H), 0.93-0.85 (m, 2H), 0.66-0.61 (m, 2H).
Example 107 Scheme 106 o 1(1 \
&
CI LiBH4 THF, Me0H

[0460] Synthesis of N-((7-chloroimidazo11,5-a1pyridin-1-yl)methyl)-1-46-cyclopropyl-8-(3-hydroxypropyl)imidazo11,2-a]pyridin-2-yl)methyl)-1H-pyrazole-carboxamide (I-107). To a solution of ethyl 3-(2((4((7-chloroimidazo[1,5-a]pyridin-1-y1) methylcarbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)propanoate (35 mg, 0.064 mmol) in THF/Me0H (5 mL/0.5 mL) was added LiBH4 (7 mg, 0.321 mmol) at 0 C. The resulting reaction was stirred at RT for 4 h. H20 (15 mL) was added to the reaction and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with prep-TLC (DCM/Me0H = 10/1) to give N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxypropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (10 mg, yield: 31%) as a white solid. ESI-MS [M+H]+: 504.2.
Purity: 97.9%. 111 NMR (400 MHz, DMS0): 6 8.58 (t, J = 5.7 Hz, 1H), 8.32-8.28 (m, 2H), 8.22-8.15 (m, 2H), 7.88 (s, 1H), 7.78 (s, 1H), 7.64 (s, 1H), 6.80 (s, 1H), 6.66-6.62 (m, 1H), 5.39 (s, 2H), 4.57-4.52 (m,
236 3H), 3.44-3.92 (m, 2H), 2.88-2.78 (m, 2H), 1.94-1.77 (m, 3H), 0.92-0.87 (m, 2H), 0.69-0.59 (m, 2H).
Example 108 Scheme 107 F Br 0H Br N
0---1( \N-N,)-1 HATU, DIPEA, DMF, rt, 2h 1-108 [0461]
Synthesis of N-((7-bromo-8-fluoroimidazo[1,5-alpyridin-1-y1)methyl)-1-((6-cyclopropylimidazo[1,2-131pyridazin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-108). A
mixture of 1((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (46 mg, 0.16 mmol), HATU (76 mg, 0.20 mmol) and DIPEA (103 mg, 0.80 mmol) in dry DMF (4 mL) was stirred at RT for 1 h. Then (7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (40 mg, 0.16 mmol) was added. The resulting mixture was stirred at RT for another 1 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to give a residue, which was purified by prep-HPLC to give N47-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide (8 mg, yield: 9.7%) as a white solid. ESI-MS [M+H]:
509.1. Purity: 98.27%. 111 NMR (400 MHz, DMS0): 6 8.46 (d, J = 2.4 Hz, 1H), 8.40 (t, J = 5.2 Hz, 1H), 8.20 (s, 1H), 8.14 (d, J = 7.4 Hz, 1H), 8.10 (s, 1H), 7.93 (d, J =
9.5 Hz, 1H), 7.83 (s, 1H), 7.11 (d, J = 9.5 Hz, 1H), 6.85-6.79 (m, 1H), 5.42 (s, 2H), 4.62 (d, J =
5.2 Hz, 2H), 2.22-2.13 (m, 1H), 1.12-1.03 (m, 2H), 1.00-0.94 (m, 2H).
237 Example 109 Scheme 108 EtO0C
CI
EtO0C
L-Nri.;NI
v N-N CH3MgEr, I I-IF
WC, 3 h HATE, DIEA, DMF
rt. 3 h CI
CI
[0462] Synthesis of ethyl 2-(24(4-(((7-chloroimidazo11,5-alpyridin-1-y1)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo11,2-alpyridin-8-y1)acetate. To a mixture of 1-((6-cyclopropy1-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.41 mmol) in DMF (3 mL) was added (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (107 mg, 0.49 mmol), DIPEA
(0.49 mL, 3 mmol) and HATU (234 mg, 0.62 mmol). The mixture was stirred at RT
for 3 h. The reaction was diluted with H20 (30 mL) and extracted with Et0Ac (30 mL x 3).
The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude which was purified by prep-TLC (DCM/Me0H = 10/1) to give ethyl 2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)acetate (70 mg, yield: 32%) as a white solid. ESI-MS
[M+H]+: 532.1.
[0463] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-46-cyclopropyl-8-(2-hydroxy-2-methylpropyl)imidazo11,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-109). To a mixture of ethyl 2-(2444(7-chloroimidazo[1,5-a]pyridin-l-y1)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)acetate (70 mg, 0.13 mmol) in THF (5 mL) was added CH3MgBr (1 M in THF, 0.65 mL, 0.65 mmol) at 0 C. The mixture was stirred at 0 C for 3 h under N2. The reaction was quenched with NH4C1 (10 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified by prep-HPLC to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (5.4 mg, yield: 8%) as a white solid. ESI-MS [M+H]+: 518.2. Purity: 99.1%. lEINIVIR
(400 MHz, DMS0): 6 8.58 (s, 1H), 8.32-8.30 (m, 2H), 8.18 (d, J = 8.3 Hz, 2H), 7.88 (s, 1H), 7.78 (s, 1H),
238 7.65 (s, 1H), 6.90 (s, 1H), 6.65 (d, J = 7.3 Hz, 1H), 5.39 (s, 2H), 5.24 (s, 1H), 4.56 (d, J = 5.2 Hz, 2H), 2.98 (s, 2H), 1.92-1.85 (m, 1H), 1.06 (s, 6H), 0.94-0.88 (m, 2H), 0.67-0.62 (m, 2H).
Example 110 Scheme 109 ,N

0 CI Nõ
f '11--1\1\\ /OH
N¨NH
Et0H, 90 C, 18 h ' 0 Cs2CO3, DMF, 55 C, 6 h Cl N NrN
H2N .\/\
CI

HATU, DIPEA, DMF, 2 h [0464] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo11,2-al pyridine.
A mixture of 5-cyclopropylpyridin-2-amine (320 mg, 2.38 mmol), 1,3-dichloropropan-2-one (906 mg, 7.14 mmol) in Et0H (5 mL) was stirred at 90 C for 18 h. Saturated aqueous NaHCO3 (20 mL) was added and the mixture was extracted with Et0Ac (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel chromatography (EA/PE = 2/1) to give 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (200 mg, yield: 41%) as a brown solid. ESI-MS [M+H]:
207.1.
[0465] Synthesis of 2-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-211-tetrazole-5-carboxylic acid. A mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (104 mg, 0.5 mmol), ethyl 1H-tetrazole-5-carboxylate (71 mg, 0.5 mmol) and Cs2CO3 (978 mg, 3 mmol) in DMF (5 mL) was stirred at 55 C for 6 h. After cooled to RT, H20 (30 mL) was added and the mixture was extracted with Et0Ac (30 mL x 3). The pH value of the H20 layer was adjusted to 5-6 by adding 1 M aqueous HC1 solution, then freeze-dried to give 2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxylic acid (71 mg, yield:
239 50%) as a yellow solid. This was used into next step without purification. ESI-MS [M+H]+:
285.1.
[0466] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-211-tetrazole-5-carboxamide (I-109). A
mixture of 2((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxylic acid (71 mg, 0.25 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (36 mg, 0.2 mmol), HATU (190 mg, 0.5 mmol) and DIPEA (97 mg, 0.75 mmol) in DIVIF (3 mL) was stirred at RT
for 2 h. Water (20 mL) was added and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by silica gel column chromatography (CH2C12/CH3OH = 10/1) to provide N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-2H-tetrazole-5-carboxamide (20.2 mg, yield: 23%) as a white solid.
ESI-MS [M+H]+:
448.1. Purity: 98.48%. 111 NMR (400 MHz, DMS0): 6 9.44 (t, J= 5.8 Hz, 1H), 8.36 (s, 1H), 8.31-8.30 (m, 2H), 7.94 (s, 1H), 7.83 (s, 1H), 7.38 (d, J = 9.3 Hz, 1H), 7.01 (dd, J = 9.4, 1.6 Hz, 1H), 6.65 (dd, J = 7.4, 2.0 Hz, 1H), 6.06 (s, 2H), 4.64 (d, J = 5.9 Hz, 2H), 1.96-1.89 (m, 1H), 1.02-0.84 (m, 2H), 0.83-0.57 (m, 2H).
Example 111 Scheme 110 0 j ( OH
N- HMI-, 0.2 h N - t-BuOH/H20. rt. 2 h ,N.61-J-' THF/Et0H/H30 N , /
50 C. 2 h 61,--1-1NN
11361 ---- \ -...}---c_R
I HNa CI
EDCI, HOBT.DIEA, / --N N--,N 0 1-111 HMI-, rt. 16 h -
240 [0467] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo11,2-blpyridazine. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (900 mg, 4.33 mmol) in dry DMF (5 mL) was added NaN3(631 mg, 9.71 mmol). The reaction mixture was stirred at RT for 2 h. Water (30 mL) was added and the mixture was extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by flash chromatography with silica gel (Et0Ac/PE =
40%) to give 2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (735 mg, yield: 79%) as dark-red oil. ESI-MS [M+H]+: 215.2.
[0468] Synthesis of ethyl 1-((6-cyclopropylimidazo11,2-blpyridazin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (730 mg, 3.41 mmol) and ethyl propiolate (501.42 mg, 5.11 mmol) in a mixture of t-BuOH/H20 (5 mL/5 mL) was added CuSO4 (543.85 mg, 3.41 mmol) and sodium ascorbate (675.05 mg, 3.41 mmol). Then the mixture was stirred at RT for 2 h. The mixture was concentrated and purified by flash silica gel chromatography (Et0Ac/PE = 10%) to give ethyl 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (600 mg, yield: 56.44%) as a red solid. ESI-MS [M+H]+: 313.2.
[0469] Synthesis of 1-((6-cyclopropylimidazo11,2-blpyridazin-2-y1)methyl)-111-1,2,3-triazole-4-carboxylic acid. To a solution of ethyl 14(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (100 mg, 0.32 mmol) in a mixture of THF/Et0H/H20 (2 mL/2 mL/1 mL) was added LiOH (15.33 mg, 0.64 mmol). The mixture was heated to 50 C for 2 h. Then the mixture was freeze-dried to give 146-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (110 mg, crude) as a white solid which was used into next step without purification. ESI-MS [M+H]: 285.1.
[0470] Synthesis of N-((7-chloroimidazo[1,5-a1pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-blpyridazin-2-y1)methyl)-111-1,2,3-triazole-4-carboxamide (I-111).
To a solution of 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (30 mg, crude from last step) in DMF (2 mL) was added EDCI
(30.35 mg, 0.158 mmol), HOBT (21.39 mg, 0.158 mmol), DIPEA (68.20 mg, 0.528 mmol) and (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (19.17 mg, 0.106 mmol). Then the mixture was stirred at RT for 16 h. Water (15 mL) was added and the mixture was extracted with ethyl acetate
241 (25 mL x 4). The combined organic layers were concentrated to give the crude product, which was purified by prep-TLC to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide (28 mg, yield: 59.09%) as a white solid. ESI-MS [M+H]: 448.2. Purity: 96%. 111NMR (400 MHz, DMS0): 6 8.91 (t, J = 5.8 Hz, 1H), 8.57 (s, 1H), 8.33-8.27 (m, 2H), 8.19 (s, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.83 (s, 1H), 7.10 (d, J = 9.4 Hz, 1H), 6.67-6.62 (m, 1H), 5.75 (s, 2H), 4.61 (d, J = 5.9 Hz, 2H), 2.22-2.13 (m, 1H), 1.12-1.02 (m, 2H), 1.00-0.94 (m, 2H).
Example 112 Scheme 111 ACc[jj¨$¨\
NaN3, DMF , N N

40 C, 3 h CuSO4, sodium ascorbate N I\L'N --Na0HTHF/H20 25 C, 16 h t-BuOH/H20, 25 C, 16h N
Cl N N N N
N \ OH fcl N HOBT EDC1, D1PEA, DMF

25 C, 16 h 1 [0471] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo11,2-al pyridine-carbonitrile. To a mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (100 mg, 0.43 mmol) in dry DMF (2 mL) was added NaN3 (39 mg, 0.65 mmol). The mixture was stirred at 25 C for 3 h. Then H20 (20 mL) was added and extracted with Et0Ac (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude, which was purified by prep-TLC (EA/PE = 3/2) to give 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (70 mg, yield: 68%) as a yellow solid. ESI-MS [M+H]: 239.2.
242 [0472] Synthesis of ethyl 1-((8-cyano-6-cyclopropylimidazo11,2-alpyridin-y1)methyl)-1H-1,2,3-triazole-4-carboxylate. To a mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (70 mg, 0.29 mmol), CuSO4 (24 mg, 0.15 mmol), sodium ascorbate (30 mg, 0.15 mmol) in t-BuOH/H20 (3/3 mL) was added ethyl propiolate (43 mg, 0.44 mmol). The mixture was stirred at 25 C for 16 h and then concentrated to give the crude product. PE/EA (10 mL/1 mL) was added, stirred at 25 C for 5 min, and a solid was filtered and washed with PE to give ethyl 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (95 mg, yield: 96%) as a yellow solid, which was used into next step without purification. ESI-MS [M+H]+: 337.2.
[0473] Synthesis of 1-((8-cyano-6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxylic acid. To a mixture of ethyl 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (95 mg, 0.28 mmol) in THF/H20 (4 mL/2 mL) was added NaOH (34 mg, 0.85 mmol). The mixture was stirred at 25 C for 16 h. The pH of the mixture was adjusted to 5 with 1 M HC1, then extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (70 mg, yield: 80%) as a grey solid. ESI-MS
[M+H]+: 309.2.
[0474] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide (I-112). To a mixture of 148-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (60 mg, 0.19 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (42 mg, 0.23 mmol), HOBT (54 mg, 0.4 mmol), EDCI (75 mg, 0.4 mmol) in DIVIF (3 mL) was added DIPEA (126 mg, 0.98 mmol). The mixture was stirred at 25 C for 16 h. Water (20 mL) was added, extracted with Et0Ac (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by prep-HPLC to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-148-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (53.7 mg, yield: 58%) as a yellow solid. ESI-MS [M+H]+: 472.1. Purity: 99.54%. 1HNMR
(400 MHz, DMS0): 6 8.94 (s, 1H), 8.69-8.60 (m, 2H), 8.31-8.30 (m, 2H), 7.99 (s, 1H), 7.84-7.80 (m, 2H), 6.65 (s, 1H), 5.81 (s, 2H), 4.63 (s, 2H), 1.98-1.97 (m, 1H), 0.96-0.95 (m, 2H), 0.76-0.75 (m, 2H).
243 Example 113 Scheme 112 .1 1 OH

1 \ Cs,CO3.PMBC1 N0,BMB _ LDA. DMF. N, i 0,-BMB
r.......¨
N . 15 tnin ________ , N
A
DCM, rt, 2 h B DMSO MB ¨ /¨ NaH, õAB, 1µ1,N
li 'MB 'MB 0 rt. 1611 r TFA. 50C. 2 h HATU).7,.,k N
) DIPEA, N / I H ../ 50C. 5 h 1µ1--,./
V' / 0H DMF (0 05M). N
.1µ1 i¨/N
HN rt, 16 h H

[0475] Synthesis of 4-methoxybenzyl 1-(4-methoxybenzy1)-1H-pyrazole-4-carboxylate. A solution of 1H-pyrazole-4-carboxylic acid (6 g, 53.53 mmol), PMBC1 (18.4 g, 117.76 mmol) and Cs2CO3 (52.3 mg, 160.59 mmol) in DMF (100 mL) was stirred at RT for 16 h. The reaction mixture was poured into H20 (600 mL) and extracted with Et0Ac (500 mL x 3).
The combined organic layers were washed with brine (200 mL), dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography (EA/PE = 1/5) to give 4-methoxybenzyl 1-(4-methoxybenzy1)-1H-pyrazole-4-carboxylate (9.8 g, yield: 52%) as a white solid. ESI-MS [M+H]+: 353.2.
[0476] Synthesis of 4-methoxybenzyl 5-formy1-1-(4-methoxybenzy1)-1H-pyrazole-4-carboxylate. To a solution of 4-methoxybenzyl 1-(4-methoxybenzy1)-1H-pyrazole-carboxylate (9.8 g, 27.81 mmol) in THF (100 mL) was added dropwise of LDA
(41.7 mL, 41.7 mmol) at -78 C over 10 min. After stirring for 5 min, DMF (12.2 g, 167.86 mmol) was added.
The resulting mixture was stirred at -78 C for another 10 min. The reaction was quenched with saturated NH4C1 aqueous (100 mL) and extracted with Et0Ac (200 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE = 1/3) to give 4-methoxybenzyl 5-formy1-1-(4-methoxybenzy1)-1H-pyrazole-4-carboxylate (4.9 g, yield: 44%) as a white solid. ESI-MS [M+H]+:
403.1.
[0477] Synthesis of 4-methoxybenzyl (E)-5-(3-ethoxy-3-oxoprop-1-en-1-y1)-1-(4-methoxybenzy1)-1H-pyrazole-4-carboxylate. To a solution of 4-methoxybenzyl 5-formy1-1-(4-
244 methoxybenzy1)-1H-pyrazole-4-carboxylate (4.9 g, 12.88 mmol) in DCM (100 mL) was added ethyl 2-(tripheny1-15-phosphanylidene)acetate (5.83 g, 16.74 mmol) in portions at 0 C. The mixture was stirred at RT for 16 h. Water (200 mL) was added and the mixture was extracted with DCM (200 mL x 3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (EA/PE = 1/3) to give m ethoxyb enzyl (E)-5-(3 -ethoxy -3 -oxoprop-1-en-l-y1)-1-(4-m ethoxyb enzy1)-1H-pyrazol e-4-carboxylate (5.7 g, 98%) as a yellow solid. ESI-MS [M+H]: 451.2.
[0478] Synthesis of 4-methoxybenzyl 5-(2-(ethoxycarbonyl)cyclopropy1)-1-(4-methoxybenzy1)-1H-pyrazole-4-carboxylate. To a suspension of NaH (102 mg, 2.68 mmol) in DMSO (10 mL) was added trimethylsulfoxonium iodide (967 mg, 4.39 mmol) at RT.
The mixture was stirred at RT for 10 mins. Then a solution of 4-methoxybenzyl (E)-5-(3-ethoxy-3-oxoprop-1-en-l-y1)-1-(4-methoxyb enzy1)-1H-pyrazol e-4-carb oxyl ate (1.1 g, 2.44 mmol) in DMSO/THF (6 mL, 1/1 (v/v)) was added. The resulting mixture was stirred at RT
for 16 h. The reaction mixture was quenched with NH4C1 aqueous (100 mL) and extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE = 1/2) to give 4-methoxybenzyl 5-(2-(ethoxycarbonyl)cyclopropy1)-1-(4-methoxybenzy1)-1H-pyrazole-4-carboxylate (1.1 g, yield:
97%) as a yellow solid. ESI-MS [M+H]: 465.2.
[0479] Synthesis of 3-(2-(ethoxycarbonyl)cyclopropy1)-1H-pyrazole-4-carboxylic acid. A solution of 4-methoxybenzyl 5-(2-(ethoxycarbonyl)cyclopropy1)-1-(4-methoxybenzy1)-1H-pyrazole-4-carboxylate (1.1 g, 2.37 mmol) in TFA (10 mL) was stirred at 50 C for 16 h. The reaction mixture was concentrated and diluted in H20 (50 mL) and the pH was adjusted to 6-7 by adding saturated NaHCO3 and then extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE = 1/3) to give 3-(2-(ethoxycarbonyl)cyclopropy1)-1H-pyrazole-4-carboxylic acid (230 mg, yield: 43%) as a yellow solid. ESI-MS [M+H]: 225.1.
[0480] Synthesis of ethyl 2-(4-(((7-chloroimidazo11,5-alpyridin-1-y1)methyl)carbamoy1)-1H-pyrazol-3-y1)cyclopropane-1-carboxylate. A mixture of 3-(2-(ethoxycarbonyl)cyclopropy1)-1H-pyrazole-4-carboxylic acid (230 mg, 1.03 mmol), (7-chloroimidazo[1,5-a]pyridin-l-yl)methanamine hydrochloride (337 mg, 1.545 mmol), HATU
245 (431 mg, 1.133 mmol) and DIPEA (399 mg, 3.09 mmol) in DMF (10 mL) was stirred at RT for 16 h. The reaction mixture was poured into H20 (120 mL) and extracted with Et0Ac/THF (80 mL x 3, 5/1 (v/v)). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (DCM/Me0H = 20/1) to give ethyl 2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-3-y1)cyclopropane-1-carboxylate (150 mg, yield: 38%) as a yellow solid. ESI-MS [M+H]+: 388.1.
[0481] Synthesis of ethyl 2-(4-(((7-chloroimidazo[1,5-a1pyridin-1-y1)methyl)carbamoy1)-1-((6-cyclopropylimidazo11,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-y1)cyclopropane-1-carboxylate (I-113). A mixture of ethyl 2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-3-y1)cyclopropane-1-carboxylate (150 mg, 0.387 mmol), 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (96 mg, 0.464 mmol) and Cs2CO3 (189 mg, 0.581 mmol) in DMF (6 mL) was stirred at 50 C for 5 h. Water (50 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (DCM/Me0H
= 8/1) to give ethyl 2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-y1)cyclopropane-1-carboxylate (110 mg, yield: 51%) as a yellow solid. ESI-MS [M+H]+: 558.2. Purity: 95.76%.
111NMR (400 MHz, DMS0): 6 8.45 (t, J = 5.6 Hz, 1H), 8.35-8.28 (m, 3H), 8.14 (s, 1H), 7.75 (m, 2H), 7.39 (d, J = 9.3 Hz, 1H), 6.99 (dd, J = 9.4, 1.7 Hz, 1H), 6.64 (dd, J = 7.4, 2.1 Hz, 1H), 5.27 (s, 2H), 4.53 (d, J = 5.7 Hz, 2H), 4.08 (q, J = 7.0 Hz, 2H), 3.22-3.16 (m, 1H), 2.01-1.95 (m, 1H), 1.91 (m, 1H), 1.41-1.32 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H), 0.94-0.88 (m, 2H), 0.69-0.63 (m, 2H).
Example 114 Scheme 113 HN /
Cs2CO3, DMF
,varN
HN
vLi\r-N CI rt 3 h N

Cl
246 [0482] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-46-cyclopropyl-8-(2-oxopyrrolidin-1-y1)imidazo11,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-114). A mixture of 1-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)pyrrolidin-2-one (25 mg, 0.087 mmol), N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (26 mg, 0.095 mmol) and Cs2CO3 (70 mg, 0.216 mmol) in DMF (3 mL) was stirred at RT for 3 h. The reaction was quenched with H20 (30 mL) was added and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified by prep-HPLC to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (16.2 mg, yield: 35%) as a white solid. ESI-MS [M+H]+: 529.2. Purity: 99.4%. 111 NMR (400 MHz, DMS0): 6 8.58 (t, J =
5.7 Hz, 1H), 8.31-8.30 (m, 2H), 8.26 (d, J = 1.2 Hz, 1H), 8.19 (s, 1H), 7.89 (s, 1H), 7.78 (d, J =
1.2 Hz, 1H), 7.71 (s, 1H), 7.16 (d, J = 1.5 Hz, 1H), 6.65 (dd, J = 7.5, 2.1 Hz, 1H), 5.41 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 4.10 (t, J = 7.1 Hz, 2H), 2.45 (t, J = 8.2 Hz, 2H), 2.14-2.03 (m, 2H), 1.95-1.88 (m, 1H), 0.98-0.89 (m, 2H), 0.68-0.59 (m, 2H).
Example 115 Scheme 114 COOEt / --N\_ \N
Cl COOEt r.........(7.4...-d) HATU,DIEA, DMF
\ N...."
_____________________________________________ 0- \ N-...õ, \N Ns-A
I\IJ,, rt,3 h ,(OH H2N N N
N=----/ 1-115 CI
[0483] Synthesis of ethyl 1-(24(4-(((7-chloroimidazo11,5-alpyridin-1-yHmethyl)carbamoy1)-1H-pyrazol-1-yHmethyl)imidazo11,2-alpyridin-8-y1)cyclopropane-1-carboxylate (I-115). A mixture of 148-(1-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (108 mg, 0.27 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrocloride (89 mg, 0.41 mmol), DIPEA (174 mg, 1.35 mmol) and HATU (205 mg, 0.54 mmol) in DMF (3 mL) was stirred at RT for 3 h. The reaction was diluted
247 with H20 (30 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified by prep-HPLC to give ethyl 1-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylate (13.4 mg, yield: 8.9%) as a white solid. ESI-MS [M+H]+: 558.2.
Purity: 98.1%. 111 NMR (400 MHz, Me0D): 6 8.25 (s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 8.09 (d, J =
2.1 Hz, 2H), 7.91 (s, 1H), 7.73 (s, 1H), 7.67 (s, 1H), 7.02 (d, J = 1.3 Hz, 1H), 6.61 (dd, J =
7.4, 1.6 Hz, 1H), 5.44 (s, 2H), 4.67 (s, 2H), 3.97 (q, J = 7.1 Hz, 2H), 1.91 (ddd, J = 13.5, 8.5, 5.2 Hz, 1H), 1.68 (dd, J =
7.2, 4.2 Hz, 2H), 1.25 (dd, J = 7.2, 4.2 Hz, 2H), 1.05-0.86 (m, 5H), 0.75-0.62 (m, 2H).
Example 116 Scheme 115 COOEt .C.20H
\ N-...." \N N -----'\ NaOH Et01-11._ ____ N-i \
N";\
RT, 3 h 14.3,1)\L71.
1-116 ¨

CI Cl [0484] Synthesis of 1-(2-04-0(7-chloroimidazo 11,5-a1pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)imidazo11,2-a] pyridin-8-yl)cyclopropane-1-carboxylic acid (I-116). To a mixture of ethyl 1-(2444(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)imidazo[1,2-a]pyridin-8-y1)cyclopropane-1-carboxylate (50 mg, 0.09 mmol) in Et0H (2 mL) was added NaOH (6.4 mg, 0.16 mmol) in H20 (1 mL). The mixture was stirred at RT for 3 h. The pH of the residue was adjusted to 4 by adding 1 M HC1 solution. The mixture was then concentrated and purified by prep-HPLC
to give the 1-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylic acid (21.6 mg, yield: 45%) as a white solid. ESI-MS [M+H]+: 530.2. Purity: 96.5%. IIINNIR (400 MHz, Me0D): 6 8.25 (s, 1H), 8.16 (d, J = 7.5 Hz, 1H), 8.11 (s, 2H), 7.91 (s, 1H), 7.73 (s, 1H), 7.67 (s, 1H), 7.09 (d, J = 1.5 Hz,
248 1H), 6.62 (dd, J= 7.5, 2.0 Hz, 1H), 5.46 (s, 2H), 4.67 (s, 2H), 1.93 (ddd, J =
13.5, 8.4, 5.1 Hz, 1H), 1.72 (dd, J = 7.1, 4.1 Hz, 2H), 1.25 (dd, J = 7.2, 4.2 Hz, 2H), 1.01-0.91 (m, 2H), 0.78-0.66 (m, 2H).
Example 117 Scheme 116 COOEt ...OH
LiBH4, THF/Me0H --"N\
___________________________________ V. \ NJ \ H2, Pd/C
_________________________________________________________________________ )..-43,1(0Bn 4Njr0Bn N=--"\N , ,.OH H2N ---- \ ..OH
/ ...-N\ / ...-N
\ N,, \N Cl J. \ N-.1 \ N"------\
NJ .,OH OH ,1( HATU, DIEA, DMF, rt, 3 h 1-117 41\1õ,:z.3.1., 1\11 .......)....... ...._Q

Cl [0485] Synthesis of benzyl 1-((8-(1-(hydroxymethyl)cyclopropyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. To a mixture of benzyl 14(841-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (266 mg, 0.6 mmol) in THF/Me0H (5 mL/0.5 mL) was added LiBH4 (136 mg, 6 mmol) at 0 C.
The mixture was stirred at 0 C for 3 h. The reaction was quenched with H20 (20 mL) and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude which was purified by prep-TLC
(DCM/MeOH: 10/1) to give benzyl 1-((8-(1-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (94 mg, yield: 38%) as a white solid.
ESI-MS [M+H]+:
403.1.
249 [0486] Synthesis of 1-08-(1-(hydroxymethyl)cyclopropyHimidazo11,2-alpyridin-2-yHmethyl)-1H-pyrazole-4-carboxylic acid. To a mixture of benzyl 14(841-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (94 mg, 0.23 mmol) in Me0H (3 mL) was added Pd/C (30 mg, 0.3 mmol). The mixture was stirred at RT for 3 h under H2. The reaction was filtered and concentrated in vacuo to give 14(841-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (70 mg, yield: 97%) as a white solid, which was used into the next step without purification. ESI-MS [M+H]+: 313.1.
[0487] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-48-(1-(hydroxymethyl)cyclopropyHimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-117). A mixture of 1-((8-(1-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (70 mg, 0.2 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (87.2 mg, 0.4 mmol), DIPEA (129 mg, 1 mmol) and HATU (152 mg, 0.4 mmol) in DMF (3 mL) was stirred at RT for 3 h. The reaction was diluted with H20 (30 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with prep-HPLC to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(1-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (26 mg, yield: 23%) as a white solid. ESI-MS [M+H]+: 516.2. Purity: 97.0%.
IIINNIR (400 MHz, Me0D): 6 8.24 (s, 1H), 8.17-8.09 (m, 2H), 8.04 (s, 1H), 7.90 (d, J = 9.6 Hz, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 6.99 (d, J = 1.3 Hz, 1H), 6.60 (dd, J = 7.5, 1.9 Hz, 1H), 5.46 (s, 2H), 4.67 (s, 2H), 3.71 (s, 2H), 1.89 (ddd, J = 13.4, 8.5, 5.1 Hz, 1H), 0.98-0.84 (m, 6H), 0.72-0.64 (m, 2H).
Example 118 Scheme 117 .&0 _....)...._oBr µ.....E0).... 0 \
N N,.-----j v.....0--Nzz..,2\1 dioxane/H20, 100 C, 2 h N. .,.../
250 [0488] Synthesis of 1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-N-((7-vinylimidazo11,5-alpyridin-1-yHmethyl)-1H-pyrazole-4-carboxamide (I-118). A
mixture of N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (50 mg, 0.16 mmol), 4,4,5,5-tetramethy1-2-viny1-1,3,2-dioxaborolane (17 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0)(23 mg, 0.02 mmol) in dioxane/H20 (2mL/0.5 mL) was stirred at 100 C for 2 h. Water (20 mL) was added and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by Prep-HPLC to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N47-vinylimidazo[1,5-a]pyridin-1-y1)methyl)-1H-pyrazole-4-carboxamide(34 mg, yield: 75%) as a white solid. ESI-MS
[M+H]+: 438.2. Purity: 93.19%. 1H NMR (400 MHz, DMSO) 6 8.52 (t, J = 5.5 Hz, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 8.25-8.17 (m, 2H), 7.86 (s, 1H), 7.71 (s, 1H), 7.55 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.02-6.96 (m, 1H), 6.94-6.88 (m, 1H), 6.68-6.57 (m, 1H), 5.77 (d, J =
17.5 Hz, 1H), 5.38 (s, 2H), 5.26 (d, J = 11.0 Hz, 1H), 4.57 (d, J = 5.6 Hz, 2H), 1.96-1.87 (m, 1H), 0.94-0.88 (m, 2H), 0.69-0.63 (m, 2H).
Example 119 Scheme 118 o r v2.
MeMgBr, THF 0H
W--;\ 0 C, 2 h N=:\
N N

[0489] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-46-cyclopropyl-8-(3-hydroxy-3-methylbutyHimidazo11,2-a]pyridin-2-yHmethyl)-1H-pyrazole-4-carboxamide (I-119). To a solution of ethyl 3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (35 mg, 0.064 mmol) in THF (3 mL) was added MeMgBr (0.32 mL, 1.0 M
251 solution in THF, 0.32 mmol) slowly 0 C. The reaction was stirred at 0 C for 2 h., quenched with aqueous NH4C1 (15 mL), and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by prep-TLC (DCM/Me0H = 10/1) to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxy-3-methylbutyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (20 mg, yield:
58.8%) as a white solid. ESI-MS [M+H]: 532.2. Purity: 95.7%. IENNIR (400 MHz, DMS0): 6 8.60 (s, 1H), 8.32-8.30 (m, 2H), 8.18 (d, J = 18.5 Hz, 2H), 7.89 (s, 1H), 7.79 (s, 1H), 7.63 (s, 1H), 6.80 (s, 1H), 6.65 (d, J = 5.5 Hz, 1H), 5.41 (s, 2H), 4.56 (s, 2H), 4.31 (s, 1H), 2.87 (s, 2H), 2.00-1.85 (m, 1H), 1.75 (s, 2H), 1.16 (s, 6H), 1.00-0.85 (m, 2H), 0.72-0.63 (m, 2H).
Example 120 Scheme 119 Li0H, H20 N N
N'N 111 N
" H Me0H, THF, NJ N
40 C, 1 h Synthesis of 2-(4-(((7-chloroimidazo 11,5-al pyridin-1-yl)methyl)carbamoy1)-1-((6-cyclopropylimidazo [1,2-alpyridin-2-yHmethyl)-1H-pyrazol-3-y1)cyclopropane-1-carboxylic acid (I-120). To a solution of ethyl 2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-y1)cyclopropane-1-carboxylate (80 mg, 0.143 mmol) in Me0H/THF/H20 (3 mL/3 mL/2 mL) was added lithium hydroxide monohydrate (30 mg, 0.717 mmol). The mixture was stirred at 40 C for 1 h. Most of the solvent was removed and the residue was diluted with H20 (10 mL). The pH of the mixture was adjusted to 4-5 by adding HC1 aqueous (1 M) and extracted with DCM/Me0H (30 mL x 3, 10/1). The combined organic layers were washed with brine, dried
252 over Na2SO4, concentrated and purified by prep-TLC (DCM/Me0H = 10/1) to give 2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-y1)cyclopropane-1-carboxylic acid (6 mg, yield: 8%) as a yellow solid.
ESI-MS [M+H]: 530.2. Purity: 95.64%. 1E1 NMR (400 MHz, DMS0): 6 12.16 (s, 1H), 8.43 (t, J
= 5.6 Hz, 1H), 8.39-8.26 (m, 3H), 8.13 (s, 1H), 7.75 (m, 2H), 7.39 (d, J = 9.3 Hz, 1H), 7.00 (dd, J
= 9.4, 1.7 Hz, 1H), 6.64 (dd, J = 7.5, 2.1 Hz, 1H), 5.27 (s, 2H), 4.60-4.48 (m, 2H), 3.21-3.13 (m, 1H), 1.96-1.85 (m, 2H), 1.36-1.29 (m, 2H), 0.91 (m, 2H), 0.72-0.63 (m, 2H).
Example 121 Scheme 120 NO NiN) NaOH, THF/H20 OH
N¨N N¨N
Cs2CO3, DMF, 25 C, 16 h 25 C, 16 h N
µN¨N
Cl 1-121 HOBt, EDCI, DIPEA, DMF 0 CI
25 C, 16h [0490]
Synthesis of methyl 24(6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-211-1,2,3-triazole-4-carboxylate. To the mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (200 mg, 0.97 mmol) in dry DMF (5 mL) was added methyl 2H-1,2,3-triazole-4-carboxylate (135 mg, 1.06 mmol) and Cs2CO3 (949 mg, 2.91 mmol). The mixture was stirred at 25 C for 16 h. Then H20 (30 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by prep-TLC (DCM/Me0H = 10/1) to give methyl 2((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazole-4-carboxylate (90 mg, yield: 31%) as a yellow solid. ESI-MS [M+H]: 298.1.
253 [0491] Synthesis of 2-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-211-1,2,3-triazole-4-carboxylic acid. To a mixture of methyl 24(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazole-4-carboxylate (90 mg, 0.3 mmol) in THF/H20 (3 mL/2 mL) was added NaOH (36 mg, 0.9 mmol). The mixture was stirred at 25 C for 16 h and the pH of the mixture was adjusted to 5 by adding 1 M HC1. The mixture was then extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give 246-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazole-4-carboxylic acid (80 mg, yield: 93%) as a yellow solid. ESI-MS [M+H]+: 284Ø
[0492] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-211-1,2,3-triazole-4-carboxamide (I-121). To a mixture of 246-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazole-4-carboxylic acid (60 mg, 0.21 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (54 mg, 0.25 mmol), HOBT (57 mg, 0.42 mmol), EDCI (81 mg, 0.42 mmol) in DMF (5 mL) was added DIPEA (135 mg, 1.04 mmol). The mixture was stirred at 25 C for 16 h.
Water (30 mL) was added and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by prep-TLC (DCM/Me0H = 10/1) to give N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-2H-1,2,3-triazole-4-carboxamide (39.1 mg, yield: 41%) as a white solid. ESI-MS [M+H]+: 447.1.
Purity: 99.57%.
1H NMR (400 MHz, DMS0): 6 8.90 (t, J = 5.8 Hz, 1H), 8.31-8.30 (m, 3H), 8.15 (s, 1H), 7.83-7.82 (m, 1H), 7.77 (s, 1H), 7.39 = 7.36 (m, 1H), 7.00-6.98 (m, 1H), 6.66-6.64 (m, 1H), 5.74 (s, 2H), 4.60 (d, J = 5.9 Hz, 2H), 1.95-1.88 (m, 1H), 0.94-0.89 (m, 2H), 0.68-0.64 (m, 2H).
Example 122 Scheme 121 N\ 0 ,vtHo NN v CI

H
N DOH, 85"C, 2 h OIN
Cs2CO3, DMF, rt, 12 h CI
254 Synthesis of 3-(2-(chloromethyl)-6-cyclopropylimidazo11,2-alpyridin-8-y1)oxetan-3-ol. To a solution of 3-(2-amino-5-cyclopropylpyridin-3-yl)oxetan-3-ol (800 mg, 3.88 mmol) in Et0H (10 mL) was added 1,3-dichloropropan-2-one (1.48 g, 11.6 mmol) at RT. The resulting reaction mixture was stirred at 85 C for 2 h. Water (30 mL) was added and the pH was adjusted to 8 by adding saturated NaHCO3 solution. The mixture was then extracted with Et0Ac (30 mL x 3).
The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (PE/Et0Ac =
1/1) to give the 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (900 mg, yield: 83%) as a light yellow oil. ESI-MS [M+H]+: 279.2.
Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-y1)methyl)-1-06-cyclopropyl-8-(3-hydroxyoxetan-3-y1)imidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-122). To a solution 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (90 mg, 0.33 mmol) in DMF (5 mL) was added N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (60 mg, 0.22 mmol) and Cs2CO3 (215 mg, 0.66 mmol) at RT. The resulting reaction mixture was stirred at RT for 12 h. Water (30 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified with prep-TLC
(DCM/Me0H = 10/1) to give the N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (20 mg, yield: 12%) as a white solid. ESI-MS [M+H]+: 518.1.
Purity: 97.8%. 111 NMR (400 MHz, DMS0): 6 8.59 (s, 1H), 8.33-8.26 (m, 3H), 8.20 (s, 1H), 7.90 (s, 1H), 7.81-7.75 (m, 1H), 7.66 (s, 1H), 7.06 (d, J = 1.6 Hz, 1H), 6.67-6.62 (m, 1H), 6.44 (s, 1H), 5.43 (s, 2H), 5.23 (d, J = 6.5 Hz, 2H), 4.63 (d, J = 6.5 Hz, 2H), 4.55 (d, J = 5.7 Hz, 2H), 1.98-1.91 (m, 1H), 0.95-0.88 (m, 2H), 0.70-0.64 (m, 2H).
255 Example 123 Scheme 122 reagent19--2?¨\N 6.Nr CHI N SN s.s C H3CN, 90 C. 10 h 43õ.1.(1õ.../1",..---,Q Dm, 00c to m 2 it CI CI

DMF. 95 C . 2 h CI

[0493] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carbothioamide. A
mixture of N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (400 mg, 0.9 mmol) and Lawesson's reagent (544 mg, 1.35 mmol) in CH3CN (10 mL) was stirred at 90 C for 16 h. The reaction mixture was cooled to RT and then filtered to provide the crude product (400 mg, yield: 96.6%) as a white solid which was used in the next step without purification. ESI-MS [M+H]+: 462.1.
[0494] Synthesis of methyl N-((7-chloroimidazo[1,5-alpyridin-1-y1)methyl)-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carbimidothioate.
To a solution of N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbothioamide (440 mg, 0.95 mmol) in DMF
(5 mL) was added NaH (76 mg, 1.9 mmol) and the reaction was stirred at 0 C for 30 min.
Then Mel (203 mg, 1.43 mmol) was added. The resulting reaction mixture was stirred at RT for 2 h. Water (30 mL) was added and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give methyl N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carbimidothioate (250 mg, crude), which was used in the next step without further purification. ESI-MS [M+H]+: 476.2.
256 [0495] Synthesis of N'4(7-chloroimidazo11,5-alpyridin-1-y1)methyl)-N-cyano-1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboximidamide (1-123). A
mixture of methyl N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carbimidothioate (250 mg, 0.53 mmol) and NH2CN (88 mg, 2.1 mmol) in DMF (3 mL) was stirred at 90 C for 2 h.
The reaction mixture was diluted with H20 (30 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated.
The crude product was purified by prep-TLC (DCM/Me0H = 10/1) to provide N'47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-N-cyano-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboximidamide (5 mg, yield: 2%). ESI-MS [M+H]+: 470.2. Purity: 90.02%. 11-1NMR (400 MHz, DMS0): 6 8.45 (s, 1H), 8.30 (s, 1H), 8.21-8.18 (m, 2H), 8.12 (s, 1H), 7.77-7.74 (m, 2H), 7.45 (d, J = 8 Hz, 1H), 7.14 (t, J = 12.0 Hz, 1H), 6.67 (m, 1H), 5.52 (s, 2H), 4.76 (s, 2H), 1.96-1.92 (m, 1H), 0.99-0.96 (m, 2H), 0.73-0.70 (s, 2H).
Example 124 Scheme 123 nA NaHCOf HO\_ese, EA Ck4-s-, MeMgBr HON_raa-Ll NH Et0H. reflux, 17 h N FEO. 1HF
HFJPC, 311 MsC1 D1PEA MsO\ .. NaNf DCM, N DM. rt FE00-BuOH

NaOH. Et0H. rt N HOBI, EDC1 N
HOA, D1PEA, DM. rt ()-1 NN EleØ_.<3 [0496] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo11,2-al pyridine. A mixture of 5-cyclopropylpyridin-2-amine (3.3 g, 25 mmol, 1.0 equiv) and 1,3-dichloropropan-2-one (12.4 g, 99 mmol, 4.0 equiv) in Et0H (60 mL) was stirred at 85 C for 16 h. The solvent was removed in vacuo. Water (100 mL) was added and extracted with Et0Ac (200 mL x 3). The combined organic layers were concentrated and purified by silica gel chromatography (PE:EA = 5:3) to
257 provide 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1.8 g, yield:
34.9%). ESI-MS
[M+H]+: 207.1.
[0497] Synthesis of (6-cyclopropylimidazo11,2-alpyridin-2-yl)methanol. A
solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1.8 g, 8.7 mmol) and NaHCO3 (5 mL, aq., sat.) in THF (10 mL) was stirred at 100 C for 16 h. Then Water (50 mL) was added and the mixture was extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated to provide (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol (1.45 g, crude) which was used in the next step without further purification. ESI-MS [M+H]+: 189.1.
[0498] Synthesis of 6-cyclopropylimidazo11,2-alpyridine-2-carbaldehyde. A
mixture of (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol (1.45 g, crude from last step) and IBX
(4.3 g, 15.4 mmol, 2.0 equiv.) in Et0Ac (50 mL) was refluxed at 80 C for 16 h. Then H20 (50 mL) was added and extracted by Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product, which was purified by silica gel chromatography (PE:EA = 2:1) to provide 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (780 mg, yield : 48% in 2 steps). ESI-MS [M+H]+: 187.1 [0499] Synthesis of 1-(6-cyclopropylimidazo[1,2-alpyridin-2-yl)ethan-1-ol. To a solution of 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (750 mg, 4.0 mmol) in THF (10 mL) was added MeMgBr (2 mL, 6.0 mmol) dropwise at 0 C. The reaction mixture was stirred at 0 C for 3 h. Then reaction mixture was quenched with saturated NH4C1 solution (10 mL) and extracted by by Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product, which was purified by silica gel chromatography (DCM:Me0H = 10:1) to give 1-(6-cyclopropylimidazo[1,2-a]pyridin-yl)ethan-l-ol (725 mg, yield: 89.7%). ESI-MS [M+H]+: 203.2.
[0500] Synthesis of 1-(6-cyclopropylimidazo11,2-alpyridin-2-yl)ethyl methanesulfonate. A mixture of 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethan-1-ol (725 mg, 3.5 mmol), DIPEA (1.35 g, 10.5 mmol) and MsC1 (519 mg, 4.55 mmol) in DCM
(20 mL) was stirred at RT for 2 h. Water (20 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude compound (980 mg, crude), which was used into the next step directly.
258 [0501] Synthesis of 2-(1-azidoethyl)-6-cyclopropylimidazo11,2-al pyridine. A mixture of 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl methanesulfonate (980 mg, crude form last step) and NaN3 (680 mg, 10.5 mmol) in DNIF (5 mL) was stirred at RT for 2 h.
Water (30 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product which was purified by prep-TLC (PE:EA = 2:1) to give 2-(1-azidoethyl)-6-cyclopropylimidazo[1,2-a]pyridine (225 mg, yield: 28% in 2 steps) as a yellow solid. ESI-MS [M+H]: 228.2.
[0502] Synthesis of ethyl 1-(1-(6-cyclopropylimidazo11,2-alpyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of 2-(1-azidoethyl)-6-cyclopropylimidazo[1,2-a]pyridine (225 mg, 0.99 mmol), ethyl propiolate (107.0 mg, 1.09 mmol), CuSO4 (173 mg, 1.09 mmol) and sodium ascorbate (200 mg, 0.99 mmol) in a mixture of t-BuOH (10 mL) and H20 (10 mL) was stirred at RT for 16 h. Solid precipitated and filtered to give ethyl 1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate (250 mg, yield:
77%) as a yellow solid. ESI-MS [M+H]: 326.2.
[0503] Synthesis of 1-(1-(6-cyclopropylimidazo11,2-alpyridin-2-yl)ethyl)-111-1,2,3-triazole-4-carboxylic acid. A mixture of ethyl 1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate (250 mg, 0.77 mmol) and NaOH (111 mg, 2.77 mmol) in THF (10 mL) and H20 (5 mL) was stirred at 50 C for 3 h. Most of the solvent was removed and the residue was diluted with H20 (5 mL). The pH of mixture was adjusted to 4-5 by adding HC1 aqueous (1 M). The precipitate was collected and dried to give the 1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid (150 mg, 65%) as a yellow solid. ESI-MS [M+H]: 298.1.
[0504] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-(1-(6-cyclopropylimidazo[1,2-alpyridin-2-y1)ethyl)-111-1,2,3-triazole-4-carboxamide (1-124). A
mixture of 1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid (150 mg, 0.51 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (132 mg, 0.61 mmol), HOBT (138 mg, 1.02 mmol), EDCI (196 mg, 1.02 mmol) and DIPEA
(329 mg, 2.55 mmol) in DMF (5 mL) was stirred at RT for 16 h. Water (50 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine and dried over Na2SO4, and concentrated. The residue was purified by prep-TLC
(DCM:Me0H =
259 10:1) to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-y1)ethyl)-1H-1,2,3-triazole-4-carboxamide (10 mg, yield: 4%). ESI-MS [M+H]+:
461.2. Purity: 100%. IENNIR (400 MHz, Me0D): 6 8.35 (s, 1H), 8.30 (s, 1H), 8.18-8.15 (m, 2H), 7.76 (s, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.12-6.07 (m, 1H), 4.75 (s, 2H), 2.02 (d, J = 8.0 Hz, 3H), 1.96-1.90 (m, 1H), 0.99-0.95 (m, 2H), 0.72-0.69 (s, 2H).
Example 125 Scheme 124 OH

s,,,,07) =,_,,õ0...e.0 [>-13' ..Z.CT,J HCv:aõ..ymi ci ci HCv,:aõ.r LIA1Ha, I HF ,..._ NH' CC(18, 2 h DMF 85"C. 1611 0"C.211 ,-- N
Br ' K3PO4, toluene/H20 reflux, 16 h HO v:Ia...1_ EB),C
isitylLOBn HN DM (10 ---:,,\N
1) Cs,CO3, F, Et0H, TEA, rt, 1611 1,130Bn r. 2 h 10,(0Bn reflux, 1611 4 j...1r0B.rt, 211 OH 0 0 N ...= 0 Mel NaH, I HF
18----)--\N
N
isi 14,3,(0Bn ,v, 10,1r0Bn ,- 743.,v0H DMF, rt, 1611 143,1c11.--Q
I-125 ¨

ci [0505]
Synthesis of ethyl 2-amino-5-bromonicotinate. To a solution of ethyl 2-aminonicotinate (25 g, 150.44 mmol) in CH3CN (500 mL) was added NBS (32.1 g, 180.5 mmol) in portions over 30 min at 0 C. The mixture was warmed to RT and stirred for 2 h. The reaction mixture was concentrated. The residue was washed with NaHCO3 aqueous (300 mL) and extracted with Et0Ac (300 mL x 3), the combined organic layers were concentrated to give ethyl 2-amino-5-bromonicotinate (36.9 g, yield: 100%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H]+: 245.1.
[0506]
Synthesis of ethyl 2-amino-5-cyclopropylnicotinate. The mixture of ethyl 2-amino-5-bromonicotinate (14.7 g, 60.18 mmol), cyclopropylboronic acid (7.75 g, 90.27 mmol), Pd(OAc)2 (1.35 g, 6.018 mmol), SPhos (4.94 g, 12.04 mmol) and K3PO4 (44.7 g, 210.58 mmol) in a mixture of toluene (200 mL) and H20 (40 mL) was stirred at 100 C for 16 h. The reaction
260 mixture was filtered through celite and the filtrate was washed with EA (100 mL) and concentrated. The crude product was purified by silica gel chromatography (EA/PE = 1/5) to give ethyl 2-amino-5-cyclopropylnicotinate (6.0 g, yield: 48%) as a yellow solid. ESI-MS
[M+H]+: 207.1.
[0507] Synthesis of (2-amino-5-cyclopropylpyridin-3-yl)methanol. To a stirred suspension of LiA1H4 (2.21 g, 58.2 mmol) in THF (120 mL) was added dropwise a solution of ethyl 2-amino-5-cyclopropylnicotinate (6.0 g, 29.1 mmol) at 0 C. The mixture was stirred at 0 C for 2 h. The reaction mixture was quenched with H20 (2.2 mL), 15% (v/v) NaOH
aqueous (2.2 mL) and H20 (6.6 mL). The mixture was stirred for 30 min at 0 C and for 2 h at RT.
Filtered and washed with Et0Ac (100 mL). The filtrate was dried, concentrated and purified by silica gel chromatography (Et0Ac) to give (2-amino-5-cyclopropylpyridin-3-yl)methanol (4.4 g, yield: 92%) as a yellow solid. ESI-MS [M+H]: 165.2.
[0508] Synthesis of (2-(chloromethyl)-6-cyclopropylimidazo11,2-alpyridin-y1)methanol. A mixture of (2-amino-5-cyclopropylpyridin-3-yl)methanol (2 g, 12.18 mmol) and 1,3-dichloropropan-2-one (4.6 g, 36.54 mmol) in DNIF (20 mL) was stirred at 85 C for 16 h.
The reaction mixture was poured into H20 (150 mL) and adjusted to pH 8 with a NaHCO3 aqueous solution and then extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE = 1/2) to give (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (913 mg, 32%) as a yellow solid. ESI-MS [M+H]: 237.1.
[0509] Synthesis of benzyl 1-06-cyclopropy1-8-(hydroxymethyl)imidazo 11,2-alpyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. A mixture of (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (730 mg, 3.08 mmol), benzyl 1H-pyrazole-4-carboxylate (624 mg, 3.08 mmol) and Cs2CO3 (1.5 g, 4.62 mmol) in DMF (10 mL) was stirred at RT for 16 h. The reaction mixture was poured into H20 (100 mL) and extracted with Et0Ac (100 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE = 1/1) to give benzyl 1-((6-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.1 g, yield: 89%) as a yellow solid. ESI-MS [M+H]: 403.2.
261 [0510] Synthesis of benzyl 1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. To a solution of benzyl 146-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.1 g, 2.73 mmol) in DCM (10 mL) was added dropwise SOC12 (1.63 mg, 13.67 mmol) at 0 C.
The mixture was stirred at for RT 1 h. The reaction mixture was concentrated. The residue was dissolved in Et0Ac (100 mL) and washed with NaHCO3 (100 mL) and brine (100 mL), dried over Na2SO4, concentrated and dried in vacuo to give benzyl 148-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.15 g, yield: 100%) as a yellow solid. ESI-MS [M+H]+: 421.1.
[0511] Synthesis of benzyl 1-((6-cyclopropy1-8-(2-ethoxy-2-oxoethyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. The mixture of benzyl 148-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.15 g, 2.73 mmol), Pd(dppf)C12 (200 mg, 0.273 mmol) and Et3N (829 mg, 8.19 mmol) in Et0H
(20 mL) was stirred at reflux for 16 h under CO. The reaction mixture was concentrated and dissolved in Et0Ac (100 mL), filtered and the filtrate was washed with H20 (50 mL) and brine (50 mL), dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE =
1/3) to give benzyl 146-cyclopropy1-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (800 mg, yield: 64%) as a yellow solid.
ESI-MS [M+H]+:
459.2.
[0512] Synthesis of benzyl 1-((6-cyclopropy1-8-(2-hydroxyethyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. To a solution of benzyl 146-cyclopropy1-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (500 mg, 1.09 mmol) in THF (10 mL) and Me0H (1 mL) was added LiBH4 (119 mg, 5.45 mmol) in portions at 0 C. The mixture was stirred at RT for 2 h. The reaction mixture was quenched with saturated NH4C1 aqueous solution (10 mL) and diluted with H20 (50 mL). the mixture was extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (Et0Ac) to give benzyl I-((6-cyclopropy1-8-(2-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (270 mg, yield: 59%) as a yellow solid. ESI-MS [M+H]+: 417.2.
262 [0513] Synthesis of benzyl 1-06-cyclopropy1-8-(2-methoxyethyl)imidazo 11,2-alpyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. To a solution of benzyl 146-cyclopropy1-8-(2-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (250 mg, 0.60 mmol) in THF (6 mL) was added NaH (48 mg, 1.2 mmol) at 0 C. After stirring for 30 min, Mel (170 mg, 1.2 mmol) in THF (1 mL) was added. The mixture was stirred at RT for 3.5 h. The reaction mixture was quenched with H20 (50 mL) and extracted with Et0Ac (50 mL
x 2). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (EA/PE = 1/2) to give benzyl 146-cyclopropy1-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (70 mg, yield:
27%) as a yellow solid. ESI-MS [M+H]+: 417.2.
[0514] Synthesis of 1-06-cyclopropy1-8-(2-methoxyethyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid. A mixture of benzyl 146-cyclopropy1-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (70 mg, 0.163 mmol) and Pd/C (30 mg) in Me0H (5 mL) was stirred at RT for 2 h under H2 (balloon). The reaction mixture was filtered and the filtrate was concentrated to give 146-cyclopropy1-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (55 mg, yield:
100%) as a yellow solid, which was used into the next step without further purification. ESI-MS
[M+H]+: 341.2.
[0515] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-46-cyclopropyl-8-(2-methoxyethyl)imidazo11,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-125). A mixture of 146-cyclopropy1-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (90 mg, 0.264 mmol), HATU
(110 mg, 0.29 mmol) and DIPEA (102 mg, 0.792 mmol) in DNIF (4 mL) was stirred at RT for 10 min. (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride hydeochloride (58 mg, 0.264 mmol) was added and stirred at RT for 16 h. Water (30 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by prep-HPLC to give N47-chloroimidazo[1,5-a]pyridin-yl)methyl)-146-cyclopropyl-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (30 mg, yield: 23%) as a white solid. ESI-MS [M+H]+:
504.2. Purity:
97.98%. 11-1 NMR (400 MHz, DMS0): 6 8.58 (t, J = 5.7 Hz, 1H), 8.34-8.27 (m, 2H), 8.22-8.15 (m, 2H), 7.87 (s, 1H), 7.79-7.75 (m, 1H), 7.65 (s, 1H), 6.86 (s, 1H), 6.64 (dd, J = 7.5, 2.1 Hz,
263 1H), 5.39 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 3.67 (t, J = 6.8 Hz, 2H), 3.21 (s, 3H), 3.04 (t, J = 6.8 Hz, 2H), 1.88 (m, 1H), 0.90 (m, 2H), 0.67-0.62 (m, 2H).
Example 126 Scheme 125 5E:OEt 0 0 EtO
CI :....1_\
NaCN
0.--- N2D4, t-BuOMe 1- CI ¨
Ac20. I 20 C 3h ) t-BuOMe. rt. 30 min "N NH
CH3CN/H20. rt. I h =N.NH
H
H
N-N N =
N LIOH-H20 ....
0 Na1\13, NH4CI \ 1 I te ________________________________ >-THF/Et0H/H20.
Cs2CO3, Ma, rt. 3 h NC Ma, I 30"C. 6 h 0Lt-'0 60C. 8 h HO `,0 CI N-N N =
N \ \ I te ______________ ).----- HN HATE, DIPEA. UN*, rt. 18 h 0 [0516] Synthesis of ethyl-4-chloro-2-(ethoxymethylene)-3-oxobutanoate. A
solution of ethyl 4-chloro-3-oxobutanoate (8 mL, 59 mmol), triethoxymethane (59 mL) and Ac20 (25 mL) was stirred at 120 C for 3 h. The reaction mixture was concentrated and n-heptane was added to the residue. Solid precipitated and was filered to give ethy1-4-chloro-2-(ethoxymethylene)-3-oxobutanoate (6 g, yield: 46%) as a yellow solid, which was used into next step without purification. ESI-MS [M+H]+: 221.2.
[0517] Synthesis of ethyl 3-(chloromethyl)-1H-pyrazole-4-carboxylate. To a solution of ethyl-4-chloro-2-(ethoxymethylene)-3-oxobutanoate (3 g, 13.6 mmol) in t-BuOMe (20 mL) was added N2H4 (3 mL). The reaction mixture was stirred at RT for 30 min. H20 (50 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product, which was purified by silica gel (PE/EA = 10/1) to obtain ethyl 3-(chloromethyl)-1H-pyrazole-4-carboxylate (1.7 g, yield: 66.5%) as a yellow solid. ESI-MS [M+H]+: 189.1.
264 [0518] Synthesis of ethyl 3-(cyanomethyl)-1H-pyrazole-4-carboxylate. To a solution of NaCN (390 mg, 8.0 mmol) in a mixture of CH3CN (20 mL) and H20 (3 mL) was added ethyl 3-(chloromethyl)-1H-pyrazole-4-carboxylate (507 mg, 2.7 mmol). The reaction mixture was stirred at RT for 1 h. Water (50 mL) was added and extracted with Et0Ac (50 mL
x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product, which was purified by C-18 reverse phase chromatography to afford ethyl 3-(cyanomethyl)-1H-pyrazole-4-carboxylate (200 mg, yield: 41%) as a white solid.
ESI-MS
[M+H]+: 180.2.
[0519] Synthesis of ethyl 3-(cyanomethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. A mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (103 mg, 0.5 mmol), ethyl 3-(cyanomethyl)-1H-pyrazole-4-carboxylate (90 mg, 0.5 mmol) and Cs2CO3 (489 mg, 3 mmol) in DMF (3 mL) was stirred at RT
for 3 h. The reaction mixture was diluted with H20 (20 mL) and extracted with Et0Ac (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product, which was purified by silica gel chromatography (CH2C12:CH3OH =
10:1) to give ethyl 3-(cyanomethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (55 mg, yield: 31%) as a brown solid. ESI-MS [M+H]+:
350.2.
[0520] Synthesis of ethyl 3-((211-tetrazol-5-y1)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. A mixture of ethyl 3-(cyanomethyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (460 mg, 1.32 mmol), NaN3 (428 mg, 6.58 mmol), NH4C1 (352 mg, 6.58 mmol) in DMF (5 mL) was stirred in a sealed tube at 130 C for 6 h. Water (50 mL) was added and extracted with Et0Ac (50 mL x 4).
The combined organic layers were concentrated to give ethyl 3-((2H-tetrazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate (121 mg, yield: 23%) as a brown solid which was used into next step without purification. ESI-MS
[M+H]+: 393.2.
[0521] Synthesis of 3-((211-tetrazol-5-y1)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl 3-((2H-tetrazol-5-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate (121 mg, 0.31 mmol) in a mixture of THF/Et0H/H20(2 mL/2 mL/1 mL) was added Li0H.H20 (26 mg, 0.62 mmol). The mixture was stirred at 60 C for 8 h. The pH of the mixture was
265 adjusted to 6 by adding 2 M aqueous HC1 solution, and was filtered to give 3-((2H-tetrazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid (96 mg, yield: 85%) as a brown solid. ESI-MS [M+H]+: 365.1.
[0522] Synthesis of 3-((211-tetrazol-5-yl)methyl)-N-((7-chloroimidazo11,5-alpyridin-1-y1)methyl)-1-((6-cyclopropylimidazo11,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-126). A mixture of 34(2H-tetrazol-5-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid (40 mg, 0.11 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (24 mg, 0.11 mmol), HOBT (28 mg, 0.22 mmol), EDCI (40 mg, 0.22 mmol) and DIPEA (72 mg, 0.55 mmol) in DIVIF
(2 mL) was stirred at RT for 18 h. Water (15 mL) was added and extracted with Et0Ac (20 mL x 3). The H20 layer was concentrated to give the crude product, which was purified by prep-HPLC to give 342H-tetrazol-5-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-y1)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (9.9 mg, yield:
17%) as a white solid. ESI-MS [M+H]+: 528.1. Purity: 98.16%. 1HNMR (400 MHz, DMS0): 6 9.08 (s, 1H), 8.32-8.28 (m, 3H), 8.17 (s, 1H), 7.76-7.75 (m, 2H), 7.39 (d, J =
9.3 Hz, 1H), 6.99 (dd, J = 9.4, 1.7 Hz, 1H), 6.63 (dd, J = 7.4, 2.0 Hz, 1H), 5.30 (s, 2H), 4.54 (d, J = 5.6 Hz, 2H), 4.36 (s, 2H), 1.95-1.88 (m, 1H), 0.93-0.88 (m, 2H), 0.68-0.64 (m, 2H).
266 Example 127 Scheme 126 vuN NH02H Bn N-%
IBX, DMS(i) N
DMF, 95"C. 3 h CI Cs2CO, DMF, rt, 3 h N NOB,40C.
4 h Nai3OBn HO
PhO

Ph 0 BnO)Isr.- 0,7/
¨S¨

N )17 Pd/C. H

IHF,rt,6h N I NaH. DMSO I HF
RI, 3 h 0 0 rt, 6 h CI
N
HATU, DIEA DMF, rt, 3 h [0523] Synthesis of (2-(chloromethyl)-6-cyclopropylimidazo11,2-alpyridin-8-y1)methanol. To a solution of (2-amino-5-cyclopropylpyridin-3-yl)methanol (4.8 g, 29 mmol) in DMF (30 mL) was added 1,3-dichloropropan-2-one (14.8 g, 117 mmol). The mixture was stirred at 95 C for 3 h. The reaction was quenched with NaHCO3 aqueous (150 mL), and extracted with Et0Ac (150 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel chromatography (Et0Ac/PE = 1/2) to give the (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (3.5 g, yield: 51%) as a white solid. ESI-MS [M+H]+: 237.1.
[0524] Synthesis of benzyl 14(6-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. The mixture of (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (3.5 g, 14.65 mmol), benzyl 1H-pyrazole-4-carboxylate (2.8 g, 14.7 mmol) and Cs2CO3 (11.9 g, 36.6 mmol) in DMF (15 mL) was stirred at RT for 3 h. The reaction was quenched with H20 (100 mL) and extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/Me0H =
10/1) to give benzyl 146-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (3.16 g, yield: 54%) as a white solid. ESI-MS
[M+H]+: 403.1.
267 [0525] Synthesis of benzyl 1-((6-cyclopropy1-8-formylimidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. The mixture of benzyl 14(6-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (3.16 g, 7.9 mmol) and MX (4.4 g, 15.7 mmol) in DMSO (15 mL) was stirred at 40 C for 4 h.
The reaction was quenched with H20 (60 mL) and extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/Me0H = 10/1) to give 1-((6-cyclopropy1-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.48 g, yield: 47%) as a yellow solid. ESI-MS [M+H]: 401.1.
[0526] Synthesis of benzyl (Z)-1-((6-cyclopropy1-8-(3-ethoxy-3-oxoprop-1-en-l-y1)imidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. To a solution of the benzyl 1((6-cyclopropy1-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.48 g, 3.7 mmol) in THF (30 mL) was added ethyl 2-(tripheny1-15-phosphanylidene)acetate (1.42 g, 41 mmol), the mixture was stirred at RT for 6 h. The reaction was concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/Me0H = 15/1) to give benzyl 146-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (890 mg , yield: 51%) as a white solid. ESI-MS
[M+H]: 471.1.
[0527] Synthesis of benzyl 1-((6-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. To a suspension of NaH (68.4 mg, 2.85 mmol) in DMSO (10 mL) was added trimethylsulfoxonium iodide (967 mg, 4.39 mmol) at RT. The mixture was stirred at RT for 10 min. Then a solution of 1-((6-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (890 mg, 1.9 mmol) in DMSO (3 mL) was added. The mixture was stirred at RT for 6 h. H20 (50 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified using a silica gel column (DCM/MeOH: 10/1) to give the benzyl 14(6-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (545 mg, yield: 59%) as a yellow solid. ESI-MS [M+H]: 485.1.
268 [0528] Synthesis of 1-06-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo 11,2-alpyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid. To a mixture of 14(6-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (545 mg, 1.13 mmol) in Me0H (10 mL) was added Pd/C (100 mg). The mixture was stirred at RT for 3 h. The reaction was filtered and concentrated in vacuo to give 1-((6-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (354 mg, yield: 80%) as a yellow solid, which was used into next step without purification. ESI-MS [M+H]+: 495.1.
[0529] Synthesis ethyl 2-(24(4-(((7-chloroimidazo11,5-alpyridin-1-y1)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo11,2-alpyridin-8-y1)cyclopropane-1-carboxylate (1-127). A mixture of 14(6-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (354 mg, 0.72 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (188 mg, 0.86 mmol), DIPEA (1 mL, 7.5 mmol) and HATU (410 mg, 1.08 mmol) in DMF (5 mL) was stirred at RT for 3 h. The reaction was diluted with H20 (30 mL) and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified with prep-TLC
(DCM/Me0H =
10/1) to give ethyl 2-(2444(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)cyclopropane-1-carboxylate (17.5 mg, yield: 4.4%) as a white solid. ESI-MS [M+H]+: 558.2. 111NMR (400 MHz, DMS0): 6 8.59 (t, J = 5.7 Hz, 1H), 8.35-8.26 (m, 2H), 8.23-8.14 (m, 2H), 7.88 (s, 1H), 7.81-7.74 (m, 1H), 7.66 (s, 1H), 6.73 (d, J = 1.4 Hz, 1H), 6.65 (dd, J = 7.5, 2.1 Hz, 1H), 5.40 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 4.09 (q, J= 7.1 Hz, 2H), 2.84-2.79 (m, 1H), 2.44-2.37 (m, 1H), 1.89-1.82 (m, 1H), 1.76-1.73 (m, 1H), 1.49-1.41 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H), 0.90-0.85 (m, 2H), 0.72-0.62 (m, 2H).
269 Example 128 vc 0 3 Scheme 127 rt CN CN CN
CI
võ.brN H2 Clrnr-"11-'1 eL() 1 N 0 N2FT-1-120 >I-0==N 0 _______________ 0 Et0H, reflux. 16 h Et0H, rt 12 h -.1µ1H2 DIPEA DCMh' NH, CI sr. CN
CN

TsCI TTN LIOH-H20 DCM, rt 5 h THF/H20 rt 1 h \N HOMDCrt1,XEA

[0530] Synthesis of ethyl 2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate. To a solution of 2-amino-5-cyclopropylnicotinonitrile (1.5 g, 9.4 mmol) in Et0H (30 mL) was added ethyl 4-chloro-3-oxobutanoate (4.0 g, 28.2 mmol) at RT and the resulting mixture was stirred at reflux for 16 h. Water (100 mL) was added to the mixture adjusted to approcimately pH 8 by adding a saturated NaHCO3 solution. Then the mixture was extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by silica gel chromatography (DCM/Me0H = 10/1) to give ethyl 2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate (1.4 g, yield: 55%) as a yellow oil. ESI-MS [M+H]+:
270.1.
[0531] Synthesis of 2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide. A mixture of ethyl 2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate (1.4 g, 5.2 mmol) and N2H4.H20 (2 mL) in Et0H (10 mL) was stirred at RT for 12 h.
The mixture was then concentrated and purified by silica gel chromatography (DCM/Me0H =
10/1) to give 2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide (1.3 g, yield:
98%) as a yellow solid, which was used in the next step without purification.
ESI-MS [M+H]+:
256.1.
[0532] Synthesis of ethyl 2-(2-(2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl)hydraziny1)-2-oxoacetate. To a solution of 2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide (700 mg, 2.7 mmol) and DIPEA (1.05 g, 8.1 mmol) in DCM (20 mL) was added ethyl 2-chloro-2-oxoacetate (561 mg, 4.1 mmol) slowly at 0 C.
The reaction mixture was stirred at RT for 2 h. Water (30 mL) was added and the mixture was extracted with DCM (50 mL x 3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (DCM/Me0H = 10/1) to give ethyl 2424248-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl)hydraziny1)-2-oxoacetate (500 mg, yield:
50%) as a yellow oil. ESI-MS [M+H]+: 356.1.
[0533] Synthesis of ethyl 5-((8-cyano-6-cyclopropylimidazo11,2-alpyridin-y1)methyl)-1,3,4-oxadiazole-2-carboxylate. To a solution of ethyl 2-(2-(2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl)hydraziny1)-2-oxoacetate (500 mg, 1.4 mmol) and Et3N (426 mg, 4.2 mmol) in DCM (10 mL) was added a solution of TsC1 (400 mg, 2.1 mmol) in DCM (5 mL) at RT, the mixture was stirred at this temperature for 16 h. Water (30 mL) was added and the mixture was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel chromatography (DCM/Me0H = 10/1) to give ethyl 54(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate (200 mg, yield:
42%) as a yellow oil. ESI-MS [M+H]+: 338.1.
[0534] Synthesis of lithium 5-((8-cyano-6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxylate. A solution of ethyl 5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate (200 mg, 0.59 mmol) and LiOH (43 mg, 1.8 mmol) in a mixture of THF/H20 (4 mL/2 mL) was stirred at RT
for 1 h. THF were concentrated and the remaining H20 phase was lyophilized to give lithium 5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate (220 mg, crude) as a red solid, which was used directly in the next step without further purification.
ESI-MS [M+H]: 310.1.
[0535] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-5-((8-cyano-6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (1-128). A
mixture of lithium 548-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate (100 mg, 0.31 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (82 mg, 0.38 mmol), EDCI (123 mg, 0.64 mmol), HOBT (86 mg, 0.64 mmol) and DIPEA (206 mg, 1.6 mmol) in DMF (5 mL) was stirred at RT for 48 h. The mixture was diluted with DCM/Me0H (30 mL, 10/1 (v/v)) and washed with H20 (20 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to give the crude
271 product, which was purified by silica gel chromatography (DCM/Me0H = 10/1) to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (25 mg, yield: 17%) as a yellow solid. ESI-MS
[M+H]+: 473.1. Purity: 96.2%. 111 NMR (400 MHz, DMS0): 6 9.77 (t, J = 5.7 Hz, 1H), 8.69 (d, J = 1.4 Hz, 1H), 8.48 (s, 1H), 8.37-8.26 (m, 2H), 8.00 (s, 1H), 7.83 (d, J =
1.9 Hz, 1H), 7.77 (d, J
= 1.6 Hz, 1H), 6.67 (dd, J = 7.4, 2.1 Hz, 1H), 4.63 (d, J = 5.8 Hz, 2H), 4.52 (s, 2H), 2.01-1.95 (m, 1H), 0.99-0.91 (m, 2H), 0.80-0.72 (m, 2H).
Example 129 Scheme 128 OH

OH
N Br pc3/3, Pd(OAc)2, K3P 4 C1C1 'krN--\\ CI

HN
Dio/H20, 90 C,16 h I DMF, 90 C, 2.5 h CI

N Nt/A111---N--XN
ArN"µ

Cs2CO3, DMF, rt, 2 h [0536] Synthesis of 5-cyclopropylpyrimidin-2-amine. To a solution of 5-bromopyrimidin-2-amine (1.0 g, 5.75 mmol) in dioxane/H20 (20 mL/3 mL) was added cyclopropylboronic acid (1.98 g, 23 mmol), palladium diacetate (134 mg, 0.63 mmol), tricyclohexyl phosphine (322 mg, 1.15 mmol) and potassium phosphate (4.24 g, 20.12 mmol).
The resulting mixture was stirred at 90 C for 16 h. The reaction was diluted with H20 (20 mL), extracted with ethyl acetate (3 x 50 mL), The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give 5-cyclopropylpyrimidin-2-amine (807 mg, yield: 95%).
ESI-MS
[M+H]+: 136.2.
[0537] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo11,2-alpyrimidine.
To a solution of 5-cyclopropylpyrimidin-2-amine (600 mg, 4.44 mmol) in DMF (5 mL) was added
272 1,3-dichloropropan-2-one (2.73 g, 22.2 mmol).The resulting mixture was stirred at 80 C for 2.5 h. The reaction mixture was diluted with H20 (50 mL), extracted with ethyl acetate (3 x 30 mL), The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give (chloromethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine (80 mg, Yield: 9%). ESI-MS [M+H]:
208.1.
[0538] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-alpyrimidin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-129). To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine (75 mg, 0.36 mmol) in DMF (2 mL) was added cesium carbonate (234 mg, 0.72 mmol), N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (97 mg, 0.36 mmol). The resulting mixture was diluted with H20 (50 mL), extracted with ethyl acetate (3 x 30 mL), The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-HPLC to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-pyrazole-4-carboxamide (15 mg, Yield:
12%) as a white solid. ESI-MS [M+H]: 447.1. Purity: 98.61%. 1HNMR (400 MHz, DMS0): 6 8.69 (d, J = 2.0 Hz, 1H), 8.60 (t, J = 5.8 Hz, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.30 (d, J = 7.2 Hz, 2H), 8.24 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 7.63 (s, 1H), 6.64 (dd, J =
7.4, 1.8 Hz, 1H), 5.43 (s, 2H), 4.55 (d, J = 5.6 Hz, 2H), 1.97 (dd, J = 8.9, 4.2 Hz, 1H), 0.97 (d, J =
6.7 Hz, 2H), 0.74 (d, J =
5.9 Hz, 2H).
273 Example 130 Scheme 129 N.5y-lis=OEt = =
CI _____________________________________________ 0Et 19,4.7./kOH
a __________________________________________________________ ).-=2*.' V..-NI-I2 DMF, 90 C, 2 5 h .õ ¨ Cs2CO3. DIME, 50 C. 2 h --"- 19"---iN 1 THF/H20. 80 C. 2 h =-...1"-=)_iN
N

H2N Na-- ====-- ci HATU, DIPEA. DMF, rt. 2 h ..õ.6... ..,, )¨/ 'q _ [0539] Synthesis of 5,6-dimethylpyridin-2-amine. To a solution of 5,6-dimethylpyridin-2-amine (1.0 g, 8.2 mmol) in DMF (10 mL) was added 1,3-dichloropropan-2-one (4.2 g, 32.8 mmol). The resulting mixture was stirred at 90 C for 2 h.
The reaction mixture was diluted with H20 (150 mL) and extracted with ethyl acetate (3 x 30 mL).
The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated.
The residue was purified by flash column chromatography to give 2-(chloromethyl)-5,6-dimethylimidazo[1,2-a]pyridine (1.0 g, yield: 63%). ESI-MS [M+H]+: 195.1.
[0540] Synthesis of ethyl 1-((5,6-dimethylimidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. To a solution of 2-(chloromethyl)-5,6-dimethylimidazo[1,2-a]pyridine (150 mg, 0.77 mmol) in DMF (5 mL) was added cesium carbonate (500 mg, 1.54 mmol), ethyl 1H-pyrazole-4-carboxylate (119 mg, 0.85 mmol). The resulting mixture was stirred at 50 C for 2 h, then diluted with H20 (50 mL), and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated.
The residue was purified by flash column chromatography to give ethyl 14(5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (200 mg, yield: 87%).
ESI-MS [M+H]: 299.2.
[0541] Synthesis of 1((5,6-dimethylimidazo[1,2-al pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (I-131). To a solution of ethyl 145,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (194 mg, 0.65 mmol) in a mixed solvent of THF/H20 (3 mL/3 mL) was added Lithium hydroxide (78 mg, 3.3 mmol). The resulting mixture was stirred
274 at 80 C for 2 h. THF was evaporated and the pH of the H20 phase was adjusted to 5 by adding 1 M HC1 solution. The resulting solid precipitate was filtered to give 145,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (160 mg, yield: 90%) which was used in the next step without further purification. ESI-MS [M+H]+: 270.1.
[0542] Synthesis of N-((7-chloroimidazo[1,2-alpyridin-2-yl)methyl)-1-((5,6-dimethylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-130).
To the solution of 1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.37 mmol) in dry DMF (5 mL) was added HATU (184 mg, 0.49 mmol), DIPEA(125 mg, 0.97 mmol) and (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (58 mg, 0.37 mmol) at RT. The reaction was stirred at RT for 2 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-HPLC to give N47-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-145,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (33.7 mg, yield: 21%).
ESI-MS [M+H]: 434.1. Purity: 99.2%. 1H NMR (400 MHz, DMS0): 6 8.80(s, 1H), 8.72(t, J =
5.5 Hz, 1H), 8.40 (d, J = 7.5 Hz, 1H), 8.38-8.32 (m, 2H), 7.98 (s, 1H), 7.95 (s, 1H), 7.84 (d, J =
9.2 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H), 6.87 (d, J = 7.4 Hz, 1H), 5.67 (s, 2H), 4.64 (d, J = 5.6 Hz, 2H), 2.67 (s, 3H), 2.42 (s, 3H).
Example 131 Scheme 130 NaN3, DMF NaOH, N N
--1\1 CI N N3 40 C, 3 h CuSO4, sodium ascorbate CN
25 C, 16 h CN CN t-BuOH/H20, 25 C, 16 h NH, Br BC!
N N
-k CN N N ic 1\ I N
3õ1,0H HOBT, EDCI, DIPEA, DMF CN
25 C, 16 h 1-131 Br
275 [0543] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo11,2-al pyridine-carbonitrile. To a mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (100 mg, 0.43 mmol) in dry DNIF (2 mL) was added NaN3 (39 mg, 0.65 mmol) and stirred at 25 C for 3 h. Then H20 (20 mL) was added and extracted with Et0Ac (20 mL x 3).
The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-TLC
(Et0Ac/PE = 3/2) to give 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (70 mg, yield: 68%) as a yellow solid. ESI-MS [M+H]+: 239.2.
[0544] Synthesis of ethyl 1-((8-cyano-6-cyclopropylimidazo11,2-alpyridin-y1)methyl)-1H-1,2,3-triazole-4-carboxylate. To a mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (70 mg, 0.29 mmol), CuSO4 (24 mg, 0.15 mmol), sodium ascorbate (30 mg, 0.15 mmol) in t-BuOH/H20 (3/3 mL) was added ethyl propiolate (43 mg, 0.44 mmol). The mixture was stirred at 25 C for 16 h. Then H20 (20 mL) was added, extracted with Et0Ac (30 mL x 3). The combined organic layers were concentrated to give ethyl 148-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (95 mg, crude) as a yellow solid. ESI-MS [M+H]: 337.2.
[0545] Synthesis of 1-((8-cyano-6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxylic acid. To a mixture of ethyl 148-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (95 mg, crude from last step) in THF/H20 (2/2 mL) was added NaOH (34 mg, 0.85 mmol). The mixture was stirred at 25 C for 16 h, 1 M HC1 was added to adjust pH about 5, extracted with Et0Ac/Me0H
(10:1, 20 mL x 3), the combined organic layers were concentrated to give 148-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (70 mg, crude) as a grey solid. ESI-MS [M+H]: 309.2.
[0546] Synthesis of N-((7-bromo-8-fluoroimidazo11,5-alpyridin-1-y1)methyl)-1-((8-cyano-6-cyclopropylimidazo11,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide (I-131). To a mixture of 148-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (70 mg, crude from last step), (7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (55 mg, 0.23 mmol), HOBT (54 mg, 0.4 mmol), EDCI (75 mg, 0.4 mmol) in DMF (3 mL) was added DIPEA (126 mg, 0.98 mmol). The mixture
276 was stirred at 25 C for 16 h. Then the reaction was poured into H20 (20 mL), the precipitate was filtered and washed with DCM (10 mL) to give N47-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-148-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (60 mg, yield: 38%) as a white solid. ESI-MS [M+H]+: 534.1.
Purity:
96.81(214nm), 98.17 (254nm). lEINIVIR (400 MHz, DMSO-d6) 6 8.73-8.69 (m, 2H), 8.59-8.50 (m, 2H), 8.14 (d, J = 6.8 Hz, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 6.82 (s, 1H), 5.81 (s, 2H), 4.70 (s, 2H), 1.99-1.98 (m, 1H), 0.97-0.96 (m, 2H), 0.76-075 (m, 2H).
Example 132 Scheme 131 HO
NaH, CH3I, CS2 S N
Cs2CO3, DMF 0 C, 4 h N RT, 14 h Bu3SnH, AIBN Li0H, THF/Et0H
________ a-Toluene, 120 C \N 50 C, 3 h s.õ HATU, DIPEA
N OH DMF, RT, 14 h CI
[0547] Synthesis of ethyl 1-06-cyclopropy1-8-(3-hydroxyoxetan-3-yl)imidazo11,2-a]pyridin-2-yHmethyl)-1H-pyrazole-4-carboxylate. A mixture of 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (1.2 g, 4.3 mmol), ethyl 1H-pyrazole-4-carboxylate (725 mg, 5.2 mmol) and Cs2CO3 (2.1 g, 6.45 mmol) in DMF (30 mL) was stirred at RT for 14h. Water (150 mL) was added to the reaction, extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to
277 give the crude product which was purified with silica gel chromatography (DCM/Me0H = 20/1) to give the ethyl 146-cyclopropy1-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.1 g, yield: 67%) as a yellow solid. ESI-MS
[M+H]+: 383.2.
[0548] Synthesis of ethyl 1-((6-cyclopropy1-8-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)imidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. To a solution of ethyl I-((6-cyclopropy1-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (600 mg, 1.57 mmol) in THF (15 mL) was added NaH (127 mg, 3.14 mmol, 60% in oil) at 0 C slowly. The resulting mixture was stirred at 0 C for 30 min.
Then CS2 (239 mg, 3.14 mmol) was added thereto at 0 C. After stirring for 30 min, CH3I (446 mg, 3.14 mmol) was added and stirred at RT for 1 h. The reaction was quenched with aqueous NH4C1, extracted with EtOAC (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the ethyl 146-cyclopropy1-8-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (650 mg crude), which was used into next step without further purification. ESI-MS [M+H]+: 473.1 [0549] Synthesis of ethyl 1-08-(oxetan-3-yl)imidazo11,2-alpyridin-2-y1)methyl)-pyrazole-4-carboxylate. A solution of ethyl 146-cyclopropy1-8-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (650 mg crude from previous step) and Bu3SnH (917 mg, 3.14 mmol) and AIBN
(515 mg, 3.14 mmol) in toluene (20 mL) was stirred at 120 C for 12 h. The reaction was concentrated in vacuo to give the residue, which was diluted with H20 (50 mL), extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product, which was purified with silica gel chromatography (EA/PE = 2/1) to give the ethyl 1-((8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (100 mg, yield: 17% over 2 steps) as a white solid. ESI-MS [M+H]+: 367.2.
[0550] Synthesis of 1-48-(oxetan-3-yl)imidazo 11,2-al pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid. A mixture of ethyl 148-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (100 mg, 0.27 mmol) and LiOH (37 mg, 1.53 mmol) in THF/H20 (10 mL/5 mL) was stirred at 50 C for 3 h. The reaction was concentrate in vacuo to give the 1-((8-
278 (oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid sodium salt (150 mg crude), which was used into next step without further purification.
ESI-MS [M+H]+:
339.1.
[0551] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-3-y1)imidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-132). To a solution of 1-((8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (150 mg, crude from previous step), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (87 mg, 0.4 mmol), HATU (177 mg, 0.47 mmol) in DMF (10 mL) was added DIPEA (200 mg, 1.55 mmol). The resulting mixture was stirred at RT for 14 h.
H20 (30 mL) was added into the reaction, extracted with EtOAC (40 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product which was purified with Prep-TLC (DCM/Me0H = 10/1) to give the N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (25 mg, yield: 18% over 2 steps) as a white solid.
ESI-MS [M+H]+:
502.2. Purity: 99.2(214nm), 99.0(254nm). 11-1NMR (400 MHz, DMSO-d6) 6 8.58 (t, J = 5.7 Hz, 1H), 8.33-8.27 (m, 2H), 8.23 (s, 1H), 8.17 (m, 1H), 7.88 (s, 1H), 7.82-7.78 (m, 1H), 7.66 (s, 1H), 7.02 (s, 1H), 6.67-6.62 (m, 1H), 5.39 (s, 2H), 4.94-4.91 (m, 2H), 4.85-4.75 (m, 2H), 4.69-4.63 (m, 1H), 4.55 (d, J = 5.7 Hz, 2H), 1.96-1.88 (m, 1H), 0.94-0.88 (m, 2H), 0.72-0.67 (m, 2H).
279 Example 133 Scheme 132 HN/Cyll'OBn N IBX

Cl..,,....).õ..C1 )._ N CI ---,7õ,..k......., I
DMF, 95 C, 3h Cs2CO3, DMF, RT, 3 h N N
x DMSO, 40 C, 4 h =\,. N....)--/
1\I \ 1 OBn HO

yl 0 Bn0 +
Ar 1 '1',..,....)..., N N 1 NaH ....., ....,N H2, Pd/C
Pli 0"
_____________________________________________________ >
N ,190,1( N 1 OBn _________________ ).--_,...
...." \
0 THF, RT, 6 h I DMSO, THF, RT, 6 h -.... N--.)¨\N Me0H, RT, 3 h 10,1(õ, OBn NH, (). )vr Cl.,,...õ .1.XHCI
/ --- ==\;.....õ,N.....f/N N ----'\
..,., ......1SN/Nali, Li0H-H20 _________________________________________________________________________ ).--HATU, DIEA, DMF, RT, 3h \ Et0H/H20, RT, 30 mm 7 n NJ,....r 19/,µ ,.........- 0 Cl --IS \N N %-"X
Nal.r1S1 ' N \
OH

[0552] Synthesis of (2-(chloromethyl)-6-cyclopropylimidazo11,2-alpyridin-8-y1)methanol.
To a solution of (2-amino-5-cyclopropylpyridin-3-yl)methanol (4.8 g, 29 mmol) in DMF (30 mL) was added 1,3-dichloropropan-2-one(14.8 g, 117 mmol) at RT and then heated at 95 'C. The reaction was monitored by LCMS until the starting material consumed (-3 h).
The reaction was cooled to RT, then quenched with NaHCO3 until pH = 8 and extracted with Et0Ac (30 mL x 3).
The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product, which was purified with flash silica gel column (eluent: Et0Ac/PE:
280 1/2) to give the (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (3.5 g, purity: 93%, yield: 51%) as a white solid. ESI-MS [M+H]+: 236.1.
[0553] Synthesis of benzyl 1-((6-cyclopropy1-8-(hydroxymethyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. A mixture of (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (3.5 g, 14.65 mmol), benzyl 1H-pyrazole-4-carboxylate (2.8 g, 14.65 mmol) and Cs2CO3 (11.9 g, 36.6 mmol) in DMF (15 mL) was stirred at RT for 3 h. The reaction was quenched with H20 (30 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product which was purified with prep-TLC (eluent:
DCM/MeOH: 10/1) to give the benzyl 146-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (3.16 g, yield: 54%) as a white solid. ESI-MS [M+H]+:
402.1.
[0554] Synthesis of benzyl 1-((6-cyclopropy1-8-formylimidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. A solution of benzyl 146-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (3.16 g, 7.9 mmol) in DMSO (15 mL) was added IBX (4.4 g, 15.7 mmol) at RT and then warmed to 40 C
and stirred for 4 h. The reaction was quenched with H20 (30 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product, which was purified with silica gel column (eluent:
DCM/MeOH: 10/1) to give the 146-cyclopropy1-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.48 g, yield: 54%) as a yellow solid. ESI-MS
[M+H]: 401.1.
[0555] Synthesis of benzyl (Z)-1-((6-cyclopropy1-8-(3-ethoxy-3-oxoprop-1-en-l-y1)imidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. A solution of the benzyl 1-((6-cyclopropy1-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.48 g, 3.7 mmol) in THF (30 mL) was added ethyl 2-(tripheny1-15-phosphanylidene)acetate (1.42 g, 41 mmol) at RT and stirred for 6 h. The reaction was concentrated in vacuo to give the crude mixture, which was purified with flash silica gel column (eluent: DCM/MeOH:
15/1) to give the benzyl 146-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (890 mg, purity: 91.5%, yield: 51%) as a white solid. ESI-MS
[M+H]: 470.1.
281 [0556] Synthesis of benzyl 1((6-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo 11,2-alpyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. A mixture of 14(6-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (890 mg, 1.9 mmol) and trimethyl sulfoxonium iodide (627 mg, 2.85 mmol) in THF/DMSO
(30/3 mL) was added NaH (190 mg, 2.85 mmol) was stirred at RT for 6 h. The reaction was quenched with H20 (30 mL) and extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product, which was purified with flash silica gel column (eluent: DCM/MeOH:
10/1) to give the benzyl 146-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (545 mg, yield: 59%) as a yellow solid. ESI-MS
[M+H]: 485.2.
[0557] Synthesis of 1((6-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo 11,2-alpyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid. A solution of 1-((6-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (545 mg, 1.13 mmol) in Me0H (10 mL) was added Pd/C (50 mg) and stirred at RT
under hydrogen for 3 h. The reaction was filtered through a pad of Celite, washed with Me0H and concentrated in vacuo to give crude 1-((6-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (354 mg, yield: 80%) as a yellow solid. ESI-MS [M+H]: 394.1.
[0558] Synthesis ethyl 2-(24(4-(((7-chloroimidazo11,5-alpyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)-6-cyclopropylimidazo11,2-alpyridin-8-y1)cyclopropane-1-carboxylate. A mixture of 1-((6-cyclopropy1-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-y1) methyl)-1H-pyrazole-4-carboxylic acid (35.4 mg, 0.09 mmol) in DNIF (3 mL) was added (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (31 mg, 0.14 mmol), DIPEA(0.1 mL, 0.75 mmol), HATU (45 mg, 0.12 mmol) and stirred at RT for 3 h. The reaction was quenched with H20 (30 mL) and extracted with Et0Ac (30 mL x 3).
The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by prep-TLC (eluent: DCM/MeOH: 10/1) to give ethyl 2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a] pyridin-8-yl)cyclopropane-1-carboxylate (17.5 mg, yield: 35%) as a white solid. ESI-MS [M+Ht 558.2. Purity: 96.0 (214nm), 95.8 (254nm). lEINIVIR
(400 MHz, DMSO-d6) 6 8.59 (t, J = 5.7 Hz, 1H), 8.35-8.26 (m, 2H), 8.23-8.14 (m, 2H), 7.88 (s, 1H), 7.81-
282 7.74 (m, 1H), 7.66 (s, 1H), 6.73 (d, J = 1.4 Hz, 1H), 6.65 (dd, J = 7.5, 2.1 Hz, 1H), 5.40 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 2.84-2.79 (m, 1H), 2.44-2.37 (m, 1H), 1.89-1.82 (m, 1H), 1.76-1.73 (m, 1H), 1.49-1.41 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H), 0.90-0.85 (m, 2H), 0.72-0.62 (m, 2H).
[0559] Synthesis of 2-(2-((4-(((7-chloroimidazo[1,5-a] pyridin-1-yl)methyl)carbamoy1)-111-pyrazol-1-yl)methyl)-6-cyclopropylimidazo [1,2-a] pyridin-8-yl)cyclopropane-1-carboxylic acid (1-133). To a mixture of ethyl 2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylate (56 mg, 0.1 mmol) in Et0H/H20 (3 mL/1 mL) was added LiORH20 (24 mg, 0.56 mmol). The mixture was stirred at RT for 30 min. After adjusting to pH
= 6 with HC1(aq), the reaction mixture was extracted with Et0Ac(30 mL x3), the combined organic layers were concentrated and the crude residue was purified by Prep-HPLC to give 2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylic acid (30 mg, yield: 57%) as a white solid. ESI-MS [M-Hr: 529.8. Purity: 97.1 (214nm), 98.0 (254nm). 1HNMR
(400 MHz, DMSO-d6) 6 11.95 (s, 1H), 8.59 (t, J= 5.5 Hz, 1H), 8.31-8.29 (m, 2H), 8.20 (s, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 7.65 (s, 1H), 6.70 (s, 1H), 6.65 (dd, J = 7.4, 1.9 Hz, 1H), 5.41 (s, 2H), 4.56 (d, J = 5.6 Hz, 2H), 2.84-2.75 (m, 1H), 2.26-2.16 (m, 1H), 1.90-1.82 (m, 1H), 1.76-1.68 (m, 1H), 1.49-1.35 (m, 1H), 0.92-1.84 (m, 2H), 0.75-0.58 (m, 2H).
Example 134 Scheme 133 &-NH2 Br HC1 H HOBT, EDCI, DIPEA, 14:3õ,e N

DMF, RT, 14 h F Br [0560] Synthesis of N-((7-bromo-8-fluoroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide (1-134). To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-
283 carboxylic acid (100 mg, 0.35 mmol), (7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (114 mg, 0.41 mmol), HOBT (67 mg, 0.49 mmol) and EDCI (94 mg, 0.49 mmol) in DMF (5 mL) was added DIPEA (226 mg, 1.75 mmol). The resulting mixture was stirred at RT for 14 h. The reaction was poured into H20 (40 mL), and yellow solid was precipitate out. The mixture was filtered and the cake was dried to give the crude product, which was triturated with DCM (25 mL) to give the N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide (65 mg, yield: 36%) as a white solid. ESI-MS [M+H]+: 509.0, purity : 98.79 (214nm), 98.38 (254nm). 111 NMR (400 MHz, DMSO-d6) 6 8.69 (t, J = 5.2 Hz, 1H), 8.55 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.14 (d, J = 7.3 Hz, 1H), 7.83 (s, 1H), 7.41 (d, J = 9.3 Hz, 1H), 7.01 (dd, J
= 9.3, 1.5 Hz, 1H), 6.83-6.80 (m, 1H), 5.73 (s, 2H), 4.69 (d, J = 5.4 Hz, 2H), 1.96-1.89 (m, 1H), 0.94-0.89 (m, 2H), 0.69-0.65 (m, 2H).
Example 135 Scheme 134 -4\1 0 ,vCr 0 0¨\
N
Et0H, 90 C
Cs2CO3, DMF, 55 C
N
Br NIN) \N_N HN
Nis 011 HOST, EDCI, '1\1 DIPEA, DMF, 40 C N 1\1=7. 1-135 [0561] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo11,2-al pyridine. A
mixture of 5-cyclopropylpyridin-2-amine (320 mg, 2.38 mmol), 1,3-dichloropropan-2-one (906 mg, 7.14 mmol) in Et0H (5 mL) was stirred at 90 C overnight. The reaction mixture was concentrated and a saturated aqueous NaHCO3 was added until pH to about 8, and then extracted with Et0Ac (50 mL x 2). The combined organic layers were concentrated and purified by silica gel
284 chromatography (EA/PE = 2/1) to give 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (200 mg, yield: 41%) as a brown solid. ESI-MS [M+H]+: 207.1.
[0562] Synthesis of 2-((6-cyclopropylimidazo 11,2-al pyridin-2-yl)methyl)-211-tetrazole-5-carboxylic acid. A mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (104 mg, 0.5 mmol), ethyl 1H-tetrazole-5-carboxylate (71 mg, 0.5 mmol) and Cs2CO3 (323 mg, 1 mmol) in DMF (3 mL) was stirred at 55 C for 6 h. Then H20 was added (10 mL), pH of the mixture was adjusted to 5 by adding HC1 (2 N), then lyophilized to give 2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxylic acid (500 mg, crude) as a yellow solid, which was used into next step without purification. ESI-MS [M+H]: 285.1.
[0563] Synthesis of N-((7-bromo-8-fluoroimidazo[1,5-alpyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-211-tetrazole-5-carboxamide (1-135). A
mixture of 2((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxylic acid (250 mg, crude from last step), (7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (45 mg, 0.16 mmol), HOBT (73 mg, 0.54 mmol), EDCI (103 mg, 0.54 mmol) and DIPEA (174 mg, 1.35 mmol) in DNIF (2 mL) was stirred at 40 C for 26 h. Water (20 mL) was added and extracted with Et0Ac (30 mL x 3), the combined organic layers were washed by H20 (10 mL), then by brine, and then concentrated, the crude was purified by prep-HPLC to give N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-246-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-2H-tetrazole-5-carboxamide (3.3 mg, yield: 4.03%) as a white solid. ESI-MS
[M+H]+: 510Ø Purity: 97.65% (214 nm), 99.08% (254 nm). IENNIR (400 MHz, DMSO-d6) 6 9.29 (t, J = 5.4 Hz, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.36 (s, 1H), 8.14 (d, J =
7.3 Hz, 1H), 7.94 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.01 (dd, J = 9.4, 1.7 Hz, 1H), 6.82 (t, J = 8 Hz, 1H), 6.06 (s, 2H), 4.71 (d, J = 5.5 Hz, 2H), 1.96-1.89 (m, 1H), 0.93-0.91 (m, 2H), 0.69-0.65 (m, 2H).
Example 136 Scheme 135 Br HC1 N¨N N
1\1 r0 NH 0 Ns AlrOLi EDCI, HOBt, DIPEA, Br DMF, 20 C 1-136
285 [0564] Synthesis of N-((7-bromo-8-fluoroimidazo[1,5-alpyridin-1-y1)methyl)-5-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (1-136). A
mixture of lithium 546-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole- 2-carboxylate (100.0 mg, 0.35 mmol), (7-bromo-8-fluoroimidazo[1,5-a]pyridin-l-y1)-methanamine hydrochloride (98.6 mg, 0.35 mmol), EDCI (134.4 mg, 0.70 mmol), HOBT (94.5 mg, 0.70 mmol) and DIPEA (0.18 mL, 1.05 mmol) in DNIF (5 mL) was stirred at 20 C for 48 h.
The mixture was concentrated to remove DMF, diluted with DCM/Me0H (300 mL, 10/1 (v/v)) and washed with H20 (100 mL x 2). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by Prep-HPLC to give N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-546-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (25.5 mg, yield: 14.3%) as a light yellow solid.
ESI-MS [M+H]: 509.9. Purity: 95.1 (214nm), 96.6 (254nm). 1H NMIt (400 MHz, DMSO-d6) 6 9.63 (t, J = 5.5 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.33 (s, 1H), 8.15 (d, J=
7.3 Hz, 1H), 7.79 (s, 1H), 7.38 (d, J = 9.3 Hz, 1H), 6.98 (dd, J = 9.3, 1.8 Hz, 1H), 6.83 (dd, J =
7.3, 6.1 Hz, 1H), 4.69 (d, J = 5.5 Hz, 2H), 4.43 (s, 2H), 1.98-1.85 (m, 1H), 1.00-0.84 (m, 2H), 0.74-0.61 (m, 2H).
Example 137 Scheme 136 OLi n\O
F NH
N
EDCI, HOBt, DIPEA, 0 DMF, 20 C 1-137 [0565] Synthesis of N-((7-bromo-8-fluoroimidazo[1,5-alpyridin-1-y1)methyl)-5-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (1-137). A
mixture of lithium 546-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole- 2-carboxylate (100.0 mg, 0.35 mmol), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (82.3 mg, 0.35 mmol), EDCI (134.4 mg, 0.70 mmol), HOBT (94.5 mg, 0.70 mmol) and DIPEA (0.18 mL, 1.05 mmol) in DNIF (5 mL) was stirred at 20 C for 48 h. The
286 mixture was concentrated to remove DMF, diluted with DCM/Me0H (300 mL, 10/1 (v/v)) and washed with H20 (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by Prep-HPLC to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide (30.0 mg, yield: 18.4%) as a white solid. ESI-MS
[M+H]+: 466.2.Purity: 97.6 (214nm), 99.1 (254nm). 1H NIVIR (400 MHz, DMSO-d6) 6 9.63 (t, J
= 5.4 Hz, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.33 (s, 1H), 8.22 (d, J = 7.4 Hz, 1H), 8.15 (s, 1H), 7.80 (s, 1H), 7.38 (d, J = 9.3 Hz, 1H), 6.98 (dd, J = 9.3, 1.7 Hz, 1H), 6.84-6.70 (m, 1H), 4.69 (d, J =
5.5 Hz, 2H), 4.43 (s, 2H), 1.93-1.87 (m, 1H), 1.01-0.85 (m, 2H), 0.75-0.55 (m, 2H).
Example 138 Scheme 137 ci.n.i >
H µ --1=1 , 2 N J'A,N 0 0 ___ > (II= N 0 N2H4, H20 N ' ___________________________________________________ )1.
N¨N N
Et0H, reflux, 16 h Et0H, reflux, 12 h H

TsCI, Et3N, DCM ..'1\1- /1=1 \
0 N¨N ir0 _________________________________________________ 0-DIPEA, DCM, 0 C to RT, 3 h H N

.4,,.¨HCI N
..C. IT-Tr\ yN
, ________________________________________________ NN..õ
====;;,... ,, õ. .N.-....õ//
LiOH Nj \
Et0H, THF, H20 N., \OLi EDCI, HOBt, DIPEA
N
N DMF, RT, 16 h 1-138 0 [0566] Synthesis of ethyl 2-(6-cyclopropylimidazo11,2-131pyridazin-2-yl)acetate. A mixture of 6-cyclopropylpyridazin-3-amine (1.00 g, 7.40 mmol) in Et0H (10 mL) was added ethyl 4-chloro-3-oxobutanoate (3.65 g, 22.19 mmol) at RT. Then the mixture was heated to 80 C and stirred for 16 h. The mixture was concentrated and purified by flash silica gel chromatography (0 ¨ 10% Me0H in DCM) to give ethyl 2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetate (1.1 g, crude) as dark-red oil. ESI-MS [M+H]+: 246.2.
287 [0567] Synthesis of 2-(6-cyclopropylimidazo11,2-131pyridazin-2-yl)acetohydrazide. To a solution of ethyl 2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetate (1.00 g, crude from last step) in Et0H (10 mL) was added hydrazine hydrate (1 mL) at RT. The mixture was heated to 80 C and stirred for 12 h. The mixture were concentrated and purified by flash silica gel chromatography (0-100% Et0Ac in PE) to give 2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetohydrazide (480 mg, 29% over 2 steps) as a red solid. ESI-MS [M+H]+:
232.1.
[0568] Synthesis of ethyl 2-(2-(2-(6-cyclopropylimidazo11,2-131pyridazin-2-yl)acetyl)hydraziny1)-2-oxoacetate. To a solution of 2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetohydrazide (477 mg, 2.06 mmol) in DCM (10 mL) was added DIPEA (533.18 mg, 4.13 mmol) and ethyl 2-chloro-2-oxoacetate (422.4 mg, 3.09 mmol) at 0 C. The mixture was stirred at 0 C for 3 h. The mixture were concentrated and purified by flash silica gel chromatography (0-10% Me0H in DCM) to give ethyl 2-(2-(2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetyl)hydraziny1)-2-oxoacetate (450 mg, yield: 65%) as a yellow solid. ESI-MS [M+H]+:
332.2.
[0569] Synthesis of ethyl 54(6-cyclopropylimidazo[1,2-131pyridazin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxylate. To a solution of ethyl 2-(2-(2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetyl)hydraziny1)-2-oxoacetate (450 mg, 1.36 mmol) in DCM
(10 mL) was added TsC1 (258 mg, 1.36 mmol), Et3N (274 mg, 2.72 mmol) at RT. The mixture was stirred for 2 h. Water (20 mL) was added and extracted with Et0Ac (30 mL x 3). The combined organic layers were concentrated and purified by flash silica gel chromatography (0-100% Et0Ac in PE) to give ethyl 5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate (240 mg, yield: 56%) as a white solid. ESI-MS [M+H]+: 314.2.
[0570] Synthesis of lithium 54(6-cyclopropylimidazo[1,2-131pyridazin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxylate. To a solution of ethyl 5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate (40 mg, 0.128 mmol) in Et0H/THF/H20 (1 mL/1 mL/1 mL) was added Li0H.H20 (10 mg, 0.255 mmol) at RT. The mixture was heated to 40 C
stirred for 0.5 h. The mixture was freeze-dried to give lithium 54(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate (50 mg, crude) as a pink solid. ESI-MS
[M+H]+: 286.1.
288 [0571] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-131pyridazin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (1-138).
To a solution of lithium 54(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate (50 mg, crude from last step) in DMF (3 mL) was added EDCI (58 mg, 0.3 mmol), HOBT (40 mg, 0.2 mmol), DIPEA (65 mg, 0.5 mmol) and (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (54 mg, 0.25 mmol) at RT. The mixture was stirred for 16 h. The mixture was concentrated and purified by Prep-HPLC to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-546-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (3 mg, yield:5%) as a white solid.
ESI-MS [M+H]+:
449Ø Purity: 98.12(214nm), 97.17(254nm). 1HNMR (400 MHz, DMSO-d6) d 9.73 (t, J = 5.8 Hz, 1H), 8.31-8.33 (m, 2H), 8.14 (s, 1H), 7.91 (d, J = 9.6 Hz, 1H), 7.84-7.82 (m, 1H), 7.08 (d, J
= 9.4 Hz, 1H), 6.69-6.65 (m, 1H), 4.62 (d, J = 5.9 Hz, 2H), 4.47 (s, 2H), 2.13-2.23 (m, 1H), 1.09-1.03 (m, 2H), 0.99-0.93 (m, 2H).
Example 139 Scheme 138 Lo li ,N3....õ..k.
N
vfle--DMF, RT, 2h --.. ,,N....._ CuSO4, sodium ascorbate, RT, 2 h N
F N
OH Br HEICI.
LiOH 2) ...--- ---)..õ...k, N- Ax11,1, N
...,././. .-." N"--. \
.....:1s1 ,1 vfõ¨

) %\
THF/Et0H/H20 ,N / EDCI, HOBT,DIEA, RT, 16 h Ni 1F\
N
F
Br [0572] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo11,2-131pyridazine. A
mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (900 mg, 4.33 mmol) in dry DMF (5 mL) was added NaN3(631 mg, 9.71 mmol) at RT. After the mixture was stirred for 2 h, H20 (50 mL)
289 was added and the mixture was extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated and purified by flash silica gel chromatography (0 ¨ 40%
Et0Ac in PE) to give 2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (735 mg, yield:
79.16%) as dark-red oil. ESI-MS [M+H]: 215.2 [0573] Synthesis of ethyl 1-((6-cyclopropylimidazo11,2-blpyridazin-2-y1)methyl)-111-1,2,3-triazole-4-carboxylate. To a solution of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (730 mg, 3.4 mmol) and ethyl propiolate (501.42 mg, 5.11 mmol) in t-BuOH/H20 (5 mL/5 mL) was added CuSO4 (543 mg, 3.4 mmol) and sodium ascorbate (675 mg, 3.41 mmol) at RT. After the mixture was stirred for 2 h, it was concentrated and purified by flash silica gel chromatography (0-10% Et0Ac in PE) to give ethyl 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (600 mg, yield: 56%) as a red solid. ESI-MS
[M+H]: 313.2.
[0574] Synthesis of 1-((6-cyclopropylimidazo11,2-blpyridazin-2-y1)methyl)-111-1,2,3-triazole-4-carboxylic acid. To a solution of ethyl 146-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (100 mg, 0.32 mmol) in THF/Et0H/H20 (0.2 mL/0.2 mL/0.2 mL) was added LiOH (15.33 mg, 0.64 mL). The mixture was heated to 50 C
for 2 h. pH
of the mixture was adjust to 5 by adding HC1 (2 M), and then the mixture was freeze-dried to give 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (110 mg, crude) as a white solid. ESI-MS [M+H]: 285.1.
[0575] Synthesis of N-((7-bromo-8-fluoroimidazo[1,5-alpyridin-1-y1)methyl)-1-((6-cyclopropylimidazo[1,2-blpyridazin-2-y1)methyl)-111-1,2,3-triazole-4-carboxamide (1-139).
To a solution of 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (110 mg, crude from last step) in DIVIF (5 mL) was added EDCI
(101 mg, 0.53 mmol), HOBT (71 mg, 0.53 mmol), DIPEA (227 mg, 1.76 mmol) and (7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (99 mg, 0.35 mmol) at RT. After the mixture was stirred for 16 h, the reaction was poured into H20, the precipitate was filtered and washed by Me0H to give N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide (25.8 mg, yield:15%) as a white solid. ESI-MS [M+H]: 510Ø Purity: 97.38(214nm), 93.35(254nm). 11-1 NMR (400 MHz, DMSO-d6) d 8.69 (t, J = 5.3 Hz, 1H), 8.56 (s, 1H), 8.45 (d, J =
2.2 Hz, 1H),
290 8.20 (s, 1H), 8.14 (d, J = 7.3 Hz, 1H), 7.94 (d, J = 9.5 Hz, 1H), 7.11 (d, J =
9.5 Hz, 1H), 6.85-6.77 (m, 1H), 5.75 (s, 2H), 4.69 (d, J = 5.5 Hz, 2H), 2.23-2.13 (m, 1H), 1.10-1.02 (m, 2H), 1.00-0.93 (m, 2H).
Example 140 Scheme 139 jrc-NH2 Br HCI
)=-=" N'") 7-0 N N
N EDCI, HOBt, DIPEA /
N N
DMF, RT, !6h 1-140 µ1\I

F Br [0576] Synthesis of N-((7-bromo-8-fluoroimidazo[1,5-alpyridin-1-y1)methyl)-5-((6-cyclopropylimidazo[1,2-blpyridazin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (I-140).
To a solution of lithium 54(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate (50 mg, crude) in DMF (3 mL) was added EDCI (58 mg, 0.3 mmol), HOBT (40 mg, 0.3 mmol), DIPEA (65 mg, 0.5 mmol) and (7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (70 mg, 0.25 mmol) at RT. The mixture was stirred for 16 h. The mixture was concentrated and purified by Prep-HPLC to give N47-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide (5 mg) as a yellow solid. ESI-MS
[M+H]+: 511Ø
Purity: 95.73(214nm), 96.89(254nm). 1H NMR (400 MHz, DMSO-d6) 6 9.63 (t, J =
5.4 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 7.4 Hz, 2H), 7.91 (d, J = 9.4 Hz, 1H), 7.09 (d, J = 9.4 Hz, 1H), 6.83 (dd, J= 7.3, 6.1 Hz, 1H), 4.69 (d, J= 5.5 Hz, 2H), 4.47 (s, 2H), 2.21 -2.14(m, 1H), 1.12-1.02 (m, 2H), 1.01-0.92 (m, 2H).
291 Example 141 Scheme 140 Br NH 2 HOC/C) >-13µ HO CI
OH
00,0 0 NH2 __ CI N n-BuLi, THF (NH2 ___________ Pd(OAc)2, Sphos DMF, 95 C, 12 h -78 C, 30 min K31304, toluene/H20 N
CI N

WI\ OH
v H:cf N

CI ___________________________________________ \
Cs2CO3, DMF, 50 C, 12 h NOyi N

CI
[0577] Synthesis of (2-amino-5-chloropyridin-3-y1)(oxetan-3-yl)methanol. To a solution of 3-bromo-5-chloropyridin-2-amine (800 mg, 3.86 mmol) in THF (20 mL) was added n-BuLi (6.4 mL, 15.5 mmol, 2.4 M solution in hexane) at -78 C and stirred for 10 min.
Then a solution of oxetane-3-carbaldehyde (1.3 g, 15.4 mmol) in 5 mL THF was added. The resulting reaction was stirred at-78 C for 5 min. The reaction was quenched with aqueous NH4C1 (20 mL), extracted with Et0Ac (50 mL x3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product, which was purified with silica gel chromatography (DCM/Me0H = 10/1) to give the (2-amino-5-chloropyridin-3-y1)(oxetan-3-yl)methanol (400 mg, yield: 48%) as a yellow solid. ESI-MS [M+H]+: 215.2.
[0578] Synthesis of (2-amino-5-cyclopropylpyridin-3-y1)(oxetan-3-yl)methanol.
A mixture of (2-amino-5-chloropyridin-3-y1)(oxetan-3-yl)methanol (400 mg, 1.87 mmol), cyclopropylboronic acid (209 mg, 2.43 mmol), Pd(OAc)2 (42 mg, 0.187 mmol), SPhos (165 mg, 0.374 mmol) and K3PO4 (1.2 g, 5.61 mmol) in toluene/H20 (25 mL/2.5 mL) was stirred at 95 C
for 14 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified with silica gel chromatography (DCM/Me0H = 10/1) to give the (2-amino-5-cyclopropylpyridin-3-y1)(oxetan-3-yl)methanol (250 mg, yield: 60.8%) as a yellow solid. ESI-MS [M+H]+: 221.2.
292 [0579] Synthesis of (2-(chloromethyl)-6-cyclopropylimidazo11,2-alpyridin-8-y1)(oxetan-3-yl)methanol. A mixture of (2-amino-5-cyclopropylpyridin-3-y1)(oxetan-3-yl)methanol (250 mg, 1.13 mmol) and 1,3-dichloropropan-2-one (572 mg, 4.5 mmol) in DNIF (10 mL) was stirred at 95 C for 12 h. H20 (30 mL) was added to the reaction, extracted with Et0Ac (30 mL x 2). The aqueous layer was free-dried to give the (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)(oxetan-3-yl)methanol (200 mg crude), which was used into next step without further purification. ESI-MS [M+H]+: 293.2 [0580] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-46-cyclopropyl-8-(hydroxy(oxetan-3-y1)methyl)imidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-141). A mixture of (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)(oxetan-3-yl)methanol (100 mg, crude from last step), N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (94 mg, 0.34 mmol) and Cs2CO3 (332 mg, 1.02 mmol) in DMF (10 mL) was stirred at 50 C for 12 h. H20 (30 mL) was added to the reaction, extracted with Et0Ac (40 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product, which was purified with Prep-HPLC to give the N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (22 mg, yield:
12%) as a white solid. ESI-MS [M+H]+: 531.9. Purity: 97.2(214nm), 95.9(254nm).
111 NMIt (400 MHz, DMSO-d6) 6 8.75-8.68 (m, 1H), 8.64-8.59 (m, 1H), 8.53-8.30 (m, 3H), 8.22-8.18 (m, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 7.63 (d, J = 6.3 Hz, 1H), 6.67-6.63 (m, 1H), 5.83-5.76 (m, 2H), 5.02-4.98 (m, 0.5H), 4.88-4.86 (m, 0.5H), 4.61-4.46 (m, 3H), 4.13-4.07 (m, 1H), 3.91-3.82 (m, 1H), 3.76-3.69 (m, 1H), 3.64-3.58 (m, 1H), 3.54-3.44 (m, 1H), 2.14-2.08 (m, 1H), 1.08-1.04 (m, 2H), 0.78-0.75 (m, 2H).
293 Example 142 Scheme 141 >¨B(OH)2 0 N)Br Dritn A \ Dr, y 3, x-,..3x 4 dioxane, H20, 100 C, 16 h H2N DMF, 90 C, 2.5 h Th\I
ci CI 0 ¨N

_.)¨zzrNH)LC171 NH NH

1) Cs2CO3, DMF, RT, 2) Me0H
[0581] Synthesis of 5-cyclopropy1-6-fluoropyridin-2-amine. To a solution of 5-bromo-6-fluoropyridin-2-amine (40 g, 209 mmol) in dioxane/H20 (400 mL/40 mL) was added cyclopropylboronic acid (36 g, 418 mmol), Pd(OAc)2 (4.7 g, 21 mmol), PCy3 (11.75 g, 42 mmol) and K3PO4 (133 g, 628 mmol), then the mixture was stirred at 100 C for 16 h.
The mixture was treated with H20 (100 mL) and extracted with Et0Ac (300 mL x 3). The organic layers were concentrated to give the crude product, which was purified by flash silica gel chromatography (PE/EA = 2/1) to give 5-cyclopropy1-6-fluoropyridin-2-amine (26 g, yield: 81%) as a white solid.
ESI-MS [M+H]: 153.1.
[0582] Synthesis of 2-(chloromethyl)-6-cyclopropy1-5-fluoroimidazo11,2-al pyridine. To a solution of 5-cyclopropy1-6-fluoropyridin-2-amine (30 g, 197 mmol) in Et0Ac (50 mL) was added 1,3-dichloropropan-2-one (32.54 g, 256 mmol), then the mixture was stirred at 60 C for 16 h. The mixture was treated with NaHCO3 (aqueous) to adjust pH to 8 and then extracted with Ethyl Acetate. The organic layer was concentrated to give the crude product which was purified by flash silica gel chromatography (PE/EA = 3:1) to give 2-(chloromethyl)-6-cyclopropy1-5-fluoroimidazo[1,2-a]pyridine (12.5 g, yield: 28%) as a white solid. ESI-MS
[M+H]: 224.9.
[0583] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropyl-5-methoxyimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide. To a solution of 2-
294 (chloromethyl)-6-cyclopropy1-5-fluoroimidazo[1,2-a]pyridine (1.94 g, 8.64 mmol) in DMF (200 mL) at RT was added N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-carboxamide (2.38 g, 8.64 mmol) and Cs2CO3(8.44 g, 25.9 mmol). The reaction mixture was stirred at RT for 16 h. The mixture was concentrated to remove DMF, diluted with Me0H (200 mL) and stirred at 60 C for 4 h and then removed Me0H, diluted with Et0Ac (200 mL), washed with H20 (200 mL). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (DCM/Me0H = 20:1 to 10:1) to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (3.5 g, yield: 85%) as a gray solid. ESI-MS [M+H]+: 476.1.Purity:
97.35 (214nm), 93.50 (254nm). lEINIVIR (400 MHz, CDC13) 6 = 8.0 (s, 2H), 7.82 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.52 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz 1H), 6.63 (t, J = 4.0 Hz 1H), 6.50 (dd, J = 7.2, 2.0 Hz, 1H), 5.45 (s, 2H), 4.74 (d, J = 5.6, 2H), 4.08 (s, 3H), 2.10-2.02 (m, 1H), 1.04-0.98 (m, 2H), 0.74-0.69 (m, 2H).
Example 143 Scheme 142 F F F F CI
OH
H2 N PC(OAC)2, PCY3, K 3 P 4 HN 2 THF, 80 C
N N Br dioxane, H20, 100 C, 16 h CI
CI
CI

NH
).1\C
N
K2CO3, DMF, 60 C CN
N
295 [0584] Synthesis of 5-cyclopropy1-3-(trifluoromethyl)pyridin-2-amine. To a solution of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (2 g, 7.2 mmol) in dioxane/H20 (100 mL/10 mL) was added cyclopropylboronic acid (1.425 g, 16.6 mmol), Pd(OAc)2 (186 mg, 0.83 mmol), PCy3 (465 mg, 1.66 mmol) and K3PO4 (3.523 g, 16.6 mmol). The reaction mixture was stirred at 100 C for 14 h under nitrogen. Then the mixture was concentrated in vacuo. Water (100 mL) was added and the mixture was extracted with Et0Ac (100 mL x 3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (PE/Et0Ac = 10/1) to give the 5-cyclopropy1-3-(trifluoromethyl)pyridin-2-amine as a yellow solid (708 mg, yield: 48%). ESI-MS [M+H]+: 203.1.
[0585] Synthesis of 2-(chloromethyl)-6-cyclopropy1-8-(trifluoromethyl)imidazo [1,2-a] pyridine. To a solution of 5-cyclopropy1-3-(trifluoromethyl)pyridin-2-amine (634 mg, 3.14 mmol) and 1,3-dichloropropan-2-one(1.194 g,9.41 mmol) in THF (30 mL) .The reaction mixture was stirred at 80 C overnight. Then H20 (50 mL) was added and extracted with Et0Ac (50 mL
x 3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (PE/Et0Ac = 10/1) to give 2-(chloromethyl)-6-cyclopropy1-8-(trifluoromethyl)imidazo[1,2-a]pyridine (232 mg, yield: 27%) as a white solid.
ESI-MS [M+H]: 275Ø
[0586] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-46-cyclopropyl-8-(trifluoromethyl)imidazo11,2-a]pyridin-2-y1)methyl)-1H-pyrazole-carboxamide (1-143). To a solution of 2-(chloromethyl)-6-cyclopropy1-8-(trifluoromethyl)imidazo[1,2-a]pyridine (126 mg, 0.45 mmol), N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (126 mg, 0.45 mmol) and K2CO3 (127 mg, 0.917 mmol) in DMF (10 mL). The resulting mixture was stirred overnight at 60 C. The mixture was concentrated to give the crude product, which was purified by silica gel chromatography (DCM/Me0H = 20/1) to give N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (58 mg, yield: 25%) as a white solid. ESI-MS [M+H]: 514.1. Purity: 95.44 (214nm), 95.85 (254nm). 1H NMR (400 MHz, Me0D) 6 8.42 (s, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 8.18 (d, J = 0.9 Hz, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.76 (s, 1H), 7.51 (s, 1H), 6.65 (dd, J =
7.5, 2.0 Hz, 1H), 5.51 (s, 2H), 4.71 (s, 2H), 2.07-1.98 (m, 1H), 1.01-0.97 (m, 2H), 0.75-0.72 (m, 2H).
296 Example 144 Scheme 143 F F >¨B(OH)2 F 0 N
DC*F, NBS
________________ 1.- N....LõBr ,,,,,, A s õ , -õ, ru3w-kC)2, rs-Y3"P `-'4 -- \---- CH3CN, 0 C, 2 h ....% dioxane, H20, 100 C, 16 h ----.
1-I2N1-I2N 1-I2N 90 C, :15 h F F

F
NaN3, DMF 0---N
/1\13 N
CuSO4, sodium ascorbate 0 CI ....... HCI CI 0 N ,N
F
Li0H, THF NcH
---Na.....õ....i....
N -:s.....õ.N.-....!/
HATU, DIPEA
N
N
1-144 I\1 F
\ ee N
[0587]
Synthesis of 5-cyclopropy1-6-fluoropyridin-2-amine. To a solution of 5-bromo-6-fluoropyridin-2-amine (40 g, 209 mmol) in dioxane/H20 (400 mL/40 mL) was added cyclopropylboronic acid (36 g, 418 mmol), Pd(OAc)2 (4.7 g, 21 mmol), PCy3 (11.75 g, 42 mmol) and K3PO4 (133 g, 628 mmol), then the mixture was stirred at 100 C for 16 h.
The mixture was treated with H20 (100 mL) and extracted with Et0Ac (300 mL x 3). The organic layers were concentrated to give the crude product, which was purified by flash silica gel chromatography (PE/EA = 2/1) to give 5-cyclopropy1-6-fluoropyridin-2-amine (26 g, yield: 81%) as a white solid.
ESI-MS [M+H]: 153.1.
[0588]
Synthesis of 2-(chloromethyl)-6-cyclopropy1-5-fluoroimidazo11,2-al pyridine.
To a solution of 5-cyclopropy1-6-fluoropyridin-2-amine (30 g, 197 mmol) in Et0Ac (50 mL) was added 1,3-dichloropropan-2-one (32.54 g, 256 mmol), then the mixture was stirred at 60 C for 16 h. The mixture was treated with NaHCO3 (aqueous) to adjust pH to 8 and then extracted with Ethyl Acetate. The organic layer was concentrated to give the crude product which was purified by flash silica gel chromatography (PE/EA = 3:1) to give 2-(chloromethyl)-6-cyclopropy1-5-fluoroimidazo[1,2-a]pyridine (12.5 g, yield: 28%) as a white solid. ESI-MS
[M+H]+: 224.9.
297 [0589] Synthesis of 2-(azidomethyl)-6-cyclopropy1-5-fluoroimidazo11,2-al pyridine.
To a solution of 2-(chloromethyl)-6-cyclopropy1-5-fluoroimidazo[1,2-a]pyridine (200 mg, 0.89 mmol) in DMF (3 mL) was added NaN3 (58 mg, 0.89 mmol), then the mixture was stirred at RT
for 5 h. Water (30 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 2-(azidomethyl)-6-cyclopropy1-5-fluoroimidazo[1,2-a]pyridine (220 mg, crude) as a white solid that was used directly in the next step. ESI-MS [M+H]+: 232.1.
[0590] Synthesis of ethyl 1-((6-cyclopropy1-5-fluoroimidazo11,2-alpyridin-y1)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of 2-(azidomethyl)-6-cyclopropy1-5-fluoroimidazo[1,2-a]pyridine (220 mg, crude) in t-BuOH/H20 (5 mL/5 mL) was added ethyl propiolate (186 mg, 1.9 mmol), CuSO4 (30 mg, 0.19 mmol) and sodium ascorbate (56 mg, 0.28 mmol), then the mixture was stirred at RT for 0.5 h. The reaction mixture showed product precipitated which was filtered and washed with H20 (10 mL) and methanol (10 mL) to give ethyl 14(6-cyclopropy1-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (250 mg, yield: 85%) as a white solid. ESI-MS [M+H]+: 330.1.
[0591] Synthesis of 1-((6-cyclopropy1-5-fluoroimidazo11,2-alpyridin-2-y1)methyl)-111-1,2,3-triazole-4-carboxylic acid. To a solution of ethyl 14(6-cyclopropy1-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (250 mg, 0.75 mmol) in THF/H20 (6 mL/3 mL) was added LiOH (42.03 mg, 1.76 mmol), then the mixture was stirred at RT overnight. The mixture was treated with HC1 (aq) to adjust the pH to 4, the precipitate was filtered and washed with H20 (10 mL) to give 14(6-cyclopropy1-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (120 mg, yield: 52%) as a white solid which was used into next step without further purification. ESI-MS [M+H]+: 302.1.
[0592] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo11,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide (1-144). To a solution of 14(6-cyclopropy1-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (60 mg, 0.2 mmol) in DMF (2 mL) was added (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (87 mg, 0.4 mmol), HATU (151 mg, 0.4 mmol) and DIPEA (154 mg, 1.19 mmol), then the mixture was stirred at RT for 0.5 h.
The reaction mixture was poured into H20 (15 mL), the solid formed, filtered and washed with
298 H20 and methanol to give N((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-14(6-cyclopropy1-5 -fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (53 mg, yield: 57%) as a white solid. ESI-MS [M+H]+: 465.1. Purity: 98.44 (214nm), 97.99 (254nm).
1H NIVIR (400 MHz, DMSO-d6) 6 8.93 (t, J = 4.0 Hz, 1H), 8.58 (s, 1H), 8.30 (brs, 2H), 7.98 (s, 1H), 7.84 (s, 1H), 7.36 (t, J = 4.0 Hz, 1H), 7.03 (t, J = 4.0 Hz, 1H), 6.65 (q, J = 4.0 Hz, 1H), 5.77 (s, 2H), 4.62 (d, J = 8.0 Hz, 2H), 2.06-2.03 (m, 1H), 0.99-0.96 (m, 2H), 0.77-0.74 (m, 2H).
Example 145 Scheme 144 A.....tõ..i.... F NCNyit'OH HATU, DIPEA

Ni3.....e....) Q

F Br [0593] Synthesis of N-((7-bromo-8-fluoroimidazo 11,5-al pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo [1,2-a] pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (1-145). To a solution of 14(6-cyclopropy1-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (60 mg, 0.2 mmol) in DMF (2 mL) was added (7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (97 mg, 0.4 mmol), HATU (151 mg, 0.4 mmol) and DIPEA (154 mg, 1.19 mmol), then the mixture was stirred at RT for 0.5 h.
The mixture was filtrated to give N47-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (62 mg, yield: 59%) as a white solid. ESI-MS [M+H]+: 527Ø Purity: 99.01 (214nm), 98.76 (254nm).
IENNIR (400 MHz, DMSO-d6) 6 8.70 (t, J = 4.0 Hz, 1H), 8.57 (s, 1H), 8.45 (d, J = 4.0 Hz, 1H), 8.13 (d, J =
4.0 Hz, 1H), 8.00 (s, 1H), 7.36 (d, J = 4.0 Hz, 1H), 7.03 (t, J = 4.0 Hz, 1H), 6.82 (t, J = 8.0 Hz, 1H), 5.77 (s, 2H), 4.70 (d, J = 4.0 Hz, 2H), 2.06-2.01 (m, 1H), 1.00-0.96 (m, 2H), 0.77-0.74 (m, 2H).
299 Example 146 Scheme 145 ci N OH
;NI EDCI, HOBT, TEA v.._ N
N N%\N
jyII
DMF, RT, overnight F
CI
[0594] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-alpyridin-1-y1)methyl)-1-((6-cyclopropylimidazo[1,2-131pyridazin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-146). A
solution of 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (105 mg, 0.37 mmol) , (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (113 mg, 0.48 mmol), EDCI (86 mg, 0.45 mmol), HOBT (60 mg, 0.45 mmol) and TEA (112 mg, 1.1 mL, 0.15 mmol) in dry DIVIF (5 mL) was stirred at RT
overnight. Then the reaction mixture was diluted with H20 (30 mL) and extracted with EtOAC 50 mL x 3). The combined organic layers were dried over Na2SO4,concentrated and purified by flash column chromatography (DCM: Me0H = 10: 1) to give the desired compound N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo [1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide (53.8 mg, yield: 31%) as a white solid.
ESI-MS [M+H]+:
465.1. Purity: 99.88 (214nm), 100.00 (254nm). 1E1 NMR (400 MHz, DMSO-d6) 6 8.44(d, J = 2.2 Hz, 1H), 8.41 (t, J = 5.0 Hz, 1H), 8.21-8.20 (m, 2H), 8.09 (s, 1H), 7.92 (d, J
= 9.4 Hz, 1H), 7.83 (s, 1H), 7.09 (d, J = 9.5 Hz, 1H), 6.76 (t, J = 6.9 Hz, 1H), 5.41 (s, 2H), 4.62 (d, J = 5.2 Hz, 2H), 2.19-2.15 (m, 1H), 1.08-1.04 (m, 2H), 0.98-0.94 (m, 2H).
Example 147 Scheme 146 jy-NH2 N CI
\N
NH
NIJI(OH _________________________________ CI
HATU, DIEA, DMF N 1-147
300 [0595] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (1-147). To a solution of 1((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (60 mg, 0.21 mmol), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (75 mg, 0.32 mmol) and HATU (120 mg, 0.31 mmol) in DMF (3 mL) was added DIPEA
(81 mg, 0.63 mmol). The resulting reaction was stirred at RT for 12 h. H20 (25 mL) was added to the reaction, extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product, which was purified with Prep-TLC (DMC/Me0H = 10/1) to give the N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (20 mg, yield: 21%) as a white solid. ESI-MS [M+H]+: 464.1. Purity:
99.3(214nm), 99.2(254nm). 11-1NWIR (400 MHz, DMSO-d6) 6 8.49-8.38 (m, 2H), 8.33 (s, 1H), 8.24-8.29 (m, 2H), 7.84 (s, 1H), 7.72 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.01-6.96 (m, 1H), 6.80-6.72 (m, 1H), 5.38 (s, 2H), 4.62 (d, J = 5.2 Hz, 2H), 1.95-1.86 (m, 1H), 0.96-0.85 (m, 2H), 0.70-0.61 (m, 2H).
Example 148 Scheme 147 jrcH2 CI HCI
N N N
NOH N
HOBT, EDCI
DIPEA, DMF
0 RT, 12 h 1-148 0 F CI
[0596] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-alpyridin-1-y1)methyl)-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide (1-148). To a suspension of 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (37 mg, 0.13 mmol) and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-yl)methanamine hydrochloride (35 mg, 0.15 mmol) in DMF (3 mL) was added HOBT
(40 mg, 0.3 mmol) and EDCI (57 mg, 0.3 mmol), followed by DIPEA (65 mg, 0.5 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was poured into H20 (15 mL) slowly.
301 The suspension mixture was stirred for 1 h, and filtered. The filtered cake was washed with H20 (20 mL) and Me0H (20 mL) then dried under vacuum pump to give the N-((7-chloro-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide as pale solid (30 mg, yield: 50%). ESI-MS
[M+H]+: 465Ø
Purity: 98.4% (214 nm), 98.5% (254 nm). lEINIVIR (400 MHz, DMSO-d6): 8.70 (t, J = 5.4 Hz, 1H), 8.55 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.35 (s, 1H), 8.21 (d, J = 7.4 Hz, 1H), 7.83 (s, 1H), 7.41 (d, J = 9.3 Hz, 1H), 7.01 (dd, J = 9.4, 1.8 Hz, 1H), 6.76 (dd, J = 7.3, 6.6 Hz, 1H), 5.73 (s, 2H), 4.70 (d, J = 5.5 Hz, 2H), 1.94-1.90 (m, 1H), 0.94-0.89 (m, 2H), 0.69-0.65 (m, 2H).
Example 149 Scheme 148 ----. NI NaN3, DMF -*".... N --) 40 C, 3 h N N3 NaOH, /
--- a CN CN CuSO4, sodium ascorbate t-BuOH/H20, 25 C, 16 h 0 Nil \:,1...1 0 _ ,...., ___________________________________________________ CN N1., 25 C, 16 h i 1......õõy--1sX21 Cl / ---i...s1")_\ j......". NI") \
.,,z.,...,.. N-...,.%N
N\
CN
...*"- --N N ______________________ a N N
N0H CN Ni -3,1c PI ---- N \
N HOBT, EDCI, DIPEA, DMF N

0 25 C, 16 h II CI
[0597] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo11,2-al pyridine-carbonitrile. To a mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (200 mg, 0.86 mmol) in DMF (5 mL) was added NaN3 (91 mg, 1.4 mmol). The mixture was stirred at 25 C for 3 h. Then H20 (30 mL) was added, extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-TLC (EA/PE
= 3/2) to give 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (140 mg, yield: 68%) as a yellow solid. ESI-MS [M+H]+: 239.2.
302 [0598] Synthesis of ethyl 1-((8-cyano-6-cyclopropylimidazo11,2-alpyridin-y1)methyl)-1H-1,2,3-triazole-4-carboxylate. To a mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (140 mg, 0.58 mmol), CuSO4 (24 mg, 0.15 mmol), sodium ascorbate (30 mg, 0.15 mmol) in t-BuOH/H20 (3/3 mL) was added ethyl propiolate (88 mg, 0.9 mmol). The mixture was stirred at 25 C for 16 h. Water (30 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give ethyl 148-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (95 mg, yield:
48%) as a yellow solid. ESI-MS [M+H]+: 337.2.
[0599] Synthesis of 1-((8-cyano-6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxylic acid. To a mixture of ethyl 148-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (95 mg, 0.28 mmol) in THF/H20 (4/2 mL) was added NaOH (34 mg, 0.85 mmol). The mixture was stirred at 25 C for 16 h. The pH of reaction was adjusted to 4 by 1 M HC1, then concentrated to give 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (130 mg, crude) as a grey solid. ESI-MS [M+H]: 309.2.
[0600] Synthesis of N-((7-chloro-8-fluoroimidazo11,5-alpyridin-1-y1)methyl)-1-((8-cyano-6-cyclopropylimidazo11,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide (1-149). To a mixture of 148-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (130 mg, crude from last step), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (58 mg, 0.25 mmol), HOBT (44 mg, 0.32 mmol), EDCI (62 mg, 0.32 mmol) in DIVIF (3 mL) was added DIPEA (103 mg, 0.8 mmol).
The mixture was stirred at 25 C for 16 h. The reaction was quenched by H20 (20 mL), extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-HPLC to give N47-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-148-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (15.6 mg, yield: 13%) as a yellow solid.
ESI-MS [M+H]: 489.9. Purity: 98.83(214nm), 99.11 (254nm). 1H NIVIR (400 MHz, DMSO-d6) 6 8.64-8.63 (m, 3H), 8.45 (s, 1H), 8.21 (s, 1H), 7.99-7.98 (m, 1H), 7.80 (s, 1H), 6.76 (s, 1H), 5.81 (s, 2H), 4.70 (s, 2H), 1.98-1.97 (m, 1H), 0.96-0.95 (m, 2H), 0.76-0.75 (m, 2H).
303 Example 150 Scheme 149 .....)..,) j ...,-- ......_N
,N:Ni ICI
NaN3 ---I\l/ vr 73 r ,vCisri--) \N
______ N DMF, RT, 2h N CuSO4, t-BuOH/H20, sodium ascorbate, RT, 2 h N

j.r--i T
a NHHc2i CI
...--- -,.- ......N N ...,..- ......N
_______________________________________________ v LiOH __ v...) \ =--...... ,N-.....% e,,,C....) \N
N --"-\
THF/Et0H/H20 41OH EDCI, HOBT,DIEA, s I \ Ii,, 3 õ..,1( NI ....)--,p 50 C, 2 h N RT, 16 h 1-150 N

F C
I
[0601] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo11,2-131pyridazine. A
mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (900 mg, 4.33 mmol) in dry DMF (5 mL) was added NaN3(631 mg, 9.71 mmol) at RT. After the mixture was stirred for 2 h.
Water (30 mL) was added and the mixture was extracted with Et0Ac (50 mL x 3).
The combined organics were concentrated and purified by flash silica gel chromatography (0 ¨ 40%
Et0Ac in PE) to give 2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (735 mg, yield:
79%) as dark-red oil. ESI-MS [M+H]+: 215.2 [0602] Synthesis of ethyl 14(6-cyclopropylimidazo[1,2-131pyridazin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (730 mg, 3.41 mmol) and ethyl propiolate (501 mg, 5.11 mmol) in t-BuOH/H20 (5 mL/5 mL) was added CuSO4 (543 mg, 3.41 mmol) and sodium ascorbate (675 mg, 3.41 mmol) at RT. After the mixture was stirred for 2 h. The mixture were concentrated and purified by flash silica gel chromatography (0-10% Et0Ac in PE) to give ethyl 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (600 mg, yield: 56%) as a red solid.
ESI-MS [M+H]: 313.2.
[0603] Synthesis of 14(6-cyclopropylimidazo[1,2-131pyridazin-2-y1)methyl)-111-1,2,3-triazole-4-carboxylic acid. To a solution of ethyl 14(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (100 mg, 0.32 mmol) in THF/Et0H/H20 (2 mL/2
304 mL/2 mL) was added LiOH (15.33 mg, 0.64 mL). The mixture was heated to 50 C
and refluxed for 2 h. HC1 (2 M) was added to adjust the pH to 4 and the mixture was freeze-dried to give 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (120 mg, crude) as a white solid. ESI-MS [M+H]+: 285.1.
[0604] Synthesis of N-((7-bromo-8-fluoroimidazo[1,5-alpyridin-1-y1)methyl)-1-((6-cyclopropylimidazo[1,2-blpyridazin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide (I-150).
To a solution of 1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (120 mg, crude from last step) in DIVIF (3 mL) was added EDCI
(111 mg, 0.58 mmol), HOBT (78 mg, 0.58 mmol), DIPEA (250.06 mg, 1.93 mmol) and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (90 mg, 0.38 mmol) at RT. After the mixture was stirred for 16 h. The mixture was poured into H20, precipitate was filtered and washed with H20 and methanol to give N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide (26.1 mg, yield:17%) as a white solid. ESI-MS [M+H]+:
466.1.Purity:
98.56(214nm), 95.15(254nm). 111NMR (400 MHz, DMSO-d6) d 8.70 (t, J = 5.4 Hz, 1H), 8.56 (s, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.23-8.17 (m, 2H), 7.94 (d, J = 9.5 Hz, 1H), 7.11 (d, J = 9.5 Hz, 1H), 6.80-6.72 (m, 1H), 5.75 (s, 2H), 4.69 (d, J = 5.5 Hz, 2H), 2.22-2.14 (m, 1H), 1.10-1.03 (m, 2H), 1.01-0.93 (m, 2H).
305 Example 151 Scheme 150 r--jC Y m-CPBA rN HNO3/H2SO4 02ry Br BrW
_______________________________________________________________________ v.-0 ).-- 1 = I NI DCM, 0 ¨ 25 C F".--.(1)00 90 C, 2 h F".--- 0 AcOH,RT, 2.5 h F-----:----6-0¨p loo C, 2 h 0 .g, )1,..... K2c03, MeOHM20 Br õ..., DMSO, COC12 Br , ,,c) H2N
Br OH
='' I ='' ___________ I 0.
F".-.--. N Et3N, DCM F...--.N Ti(0E04 F.-..-..- N
THF, 80 C

II II TFA Bry,-.,z,,rõ-^, HCOOH
Br ,,... `,NõS- NaBH4 Br NH2 I N _),,.. I -).....
F"---..- N
F--.---.

õ.^.,:õ., N
F
0 N..*
Br Br H2N.gt ----"N
NH POC13 ''",,--,_-.%\ POC13, DMF Br N
Br,,,..,,,,õ,r_i F N 0 100 C, 2h F"..-......'-'''' N--- FN Ti(0E04 N
THF, 80 C,16 h F"---''.."'"'N

0\\

N N
NaBH4 j. NH TFA 3., Brs..,õ,r5r HOBT, EDCI 1 N
Me0H, RT, 3 h Br ../ --- 16h .õ--.. FN,-......% DIPEA, DMF
,N \ / 1-151 N - . . . .1/
F Br F
[0605]
Synthesis of 5-fluoro-2-methylpyridine 1-oxide. To a stirred solution of 5-fluoro-2-methylpyridine (5 g, 45 mmol) in DCM (100 mL) was added m-CPBA (11.6 g, 67.5 mmol) at 0 C and the mixture was stirred at 25 C for 16 h. The mixture was quenched with saturated aqueous Na2S203, stirred vigorously for 15 min, and then poured into saturated aqueous NaHCO3. The layers were separated, and the aqueous layer was extracted twice more with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated to give 5-fluoro-2-methylpyridine 1-oxide (4.7 g, 82 %) as a yellow solid which was used into next step without further purification. ESI-MS [M+H]+: 128.2.
306 [0606] Synthesis of 5-fluoro-2-methyl-4-nitropyridine 1-oxide.
Concentrated H2 SO4 (15 mL) was slowly added to 5-fluoro-2-methylpyridine 1-oxide (4.7 g, 37 mmol) at 0 C. A
mixture of fuming HNO3 (10 mL) and concentrated H2SO4 (15 mL) was then added dropwise to the mixture at 0 C. Then the mixture was heated to 90 C for 16 h. The mixture was slowly poured into 400 g of ice and then neutralized with solid NH4HCO3. The mixture was extracted three times with DCM, and the combined organic layers were dried over MgSO4, filtered and concentrated to give 5-fluoro-2-methyl-4-nitropyridine 1-oxide (4.7 g, 74 %) as a yellow solid which was used without further purification. ESI-MS [M+H]+: 173.1.
[0607] Synthesis of 4-bromo-5-fluoro-2-methylpyridine 1-oxide. To a solution of 5-fluoro-2-methy1-4-nitropyridine 1-oxide (4.7 g, 27.3 mmol) in acetic acid (40 mL) was added acetyl bromide (15 mL) dropwise over 5 mins. After addition, the mixture was stirred at 80 C
for 16 h. The reaction mixture was poured into ice and the solution basified to pH 8 with cold 2 M sodium hydroxide. The aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 4-bromo-5-fluoro-2-methylpyridine 1-oxide (5.5 g, 98 %) as a yellow solid. ESI-MS [M+H]+:
206Ø
[0608] Synthesis of (4-bromo-5-fluoropyridin-2-yl)methyl acetate. A
mixture of 4-bromo-5-fluoro-2-methylpyridine 1-oxide (5.5 g, 26.8 mmol) in acetic anhydride (30 mL) was stirred at 100 C for 2 h, then cooled to 25 C, concentrated to give the crude product, NaHCO3 (aq) was added to adjust pH about 9, extracted with DCM (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product which was purified by column chromatography (PE:EA = 20:1 to 10:1) to give (4-bromo-5-fluoropyridin-2-yl)methyl acetate (3.2 g, yield: 48%) as a yellow oil . ESI-MS [M+H]+:
248.1.
[0609] Synthesis of (4-bromo-5-fluoropyridin-2-yl)methanol. To a mixture of (4-bromo-5-fluoropyridin-2-yl)methyl acetate (2.5 g, 10 mmol) in Me0H/H20 (20/2 mL) was added K2CO3 (7 g, 50 mmol). The mixture was stirred at 25 C for 16 h. Then Me0H was remove. Water (20 mL) was added, extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give (4-bromo-5-
307 fluoropyridin-2-yl)methanol (2 g, yield: 96%) as a yellow oil which was used into next step without further purification.. ESI-MS [M+H]+: 206Ø
[0610] Synthesis of 4-bromo-5-fluoropicolinaldehyde. To a solution of oxalyl chloride (1.86 g, 14.6 mmol) in DCM (50 mL) under nitrogen was added dropwise a solution of DMSO
(1.52 g, 19.5 mmol) in DCM (20 mL) at -78 C. Stirring was continued for 10 minutes. A
solution of (4-bromo-5-fluoropyridin-2-yl)methanol (2 g, 9.76 mmol) in DCM (20 mL) was then added dropwise over 20 minutes. The reaction was stirred for 1 h.
Triethylamine (4.93 g, 48.8 mmol) was added dropwise and the reaction was allowed to warm to RT over 1.5 h. The reaction was then quenched by addition of H20 (50 mL). The organics were separated and H20 phase was extracted with DCM (50 mL x 2). Concentrated in vacuo to give 4-bromo-5-fluoropicolinaldehyde (1.2 g, yield: 59%) as a brown oil which was used into next step without further purification. ESI-MS [M+H]+: 204.2 [0611] Synthesis of (E)-N-((4-bromo-5-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. To a mixture of 4-bromo-5-fluoropicolinaldehyde (1.2 g, 5.9 mmol), 2-methylpropane-2-sulfinamide (857 mg, 7.08 mmol) in dry THF (20 mL) was added Ti(0E04 (4.03 g, 17.7 mmol). The mixture was stirred at 75 C for 16 h. Water (100 mL) was added and extracted with Et0Ac(100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give (E)-N-((4-bromo-5-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.8 g, crude). ESI-MS [M+H]+:
307.1 [0612] Synthesis of N-((4-bromo-5-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide. To a mixture of (E)-N44-bromo-5-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.8 g, crude from last step) in dry THF (30 mL) was added NaBH4 (897 mg, 23.6 mmol). The mixture was stirred at 25 C for 3 h. Then H20 (20 mL) was added, extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-TLC (DCM/Me0H = 10/1) to give N44-bromo-5-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (900 mg, yield: 50% over 2 steps) as a yellow oil.
ESI-MS
[M+H]+: 309Ø
[0613] Synthesis of (4-bromo-5-fluoropyridin-2-yl)methanamine. A mixture of N-((4-bromo-5-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (900 mg, 2.92 mmol) in
308 TFA (10 mL) was stirred at 40 C for 16 h. Then concentrated to give (4-bromo-5-fluoropyridin-2-yl)methanamine (590 mg, yield: 99%) as a yellow oil which was used in the next step without further purification.. ESI-MS [M+H]+: 205.1.
[0614] Synthesis of N-((4-bromo-5-fluoropyridin-2-yl)methyl)formamide. A
mixture of (4-bromo-5-fluoropyridin-2-yl)methanamine (590 mg, 2.89 mmol) in HCOOH (10 mL) was stirred at 90 C for 3 h. Then concentrated to give the crude product, which was purified by Prep-TLC (DCM/Me0H = 10/1) to give N((4-bromo-5-fluoropyridin-2-yl)methyl)formamide (400 mg, yield: 60%) as a yellow solid. ESI-MS [M+H]+: 233.1.
[0615] Synthesis of 7-bromo-6-fluoroimidazo 11,5-al pyridine. A mixture of N-((4-bromo-5-fluoropyridin-2-yl)methyl)formamide (400 mg, 1.72 mmol) in POC13 (10 mL) was stirred at 100 C for 1 h. Then POC13 was concentrated, H20 (20 mL) was added, followed by Na2CO3 (aq) to adjust pH about 8, extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated.
The crude product was purified by Prep-TLC (EA/PE = 2/1) to give 7-bromo-6-fluoroimidazo[1,5-a]pyridine (300 mg, yield: 81%) as a yellow solid. ESI-MS [M+H]+: 215Ø
[0616] Synthesis of 7-bromo-6-fluoroimidazo[1,5-alpyridine-1-carbaldehyde. To a mixture of 7-bromo-6-fluoroimidazo[1,5-a]pyridine (300 mg, 1.4 mmol) in dry DMF (1 mL) was added POC13 (321 mg, 2.1 mmol). The mixture was stirred at 100 C for 1 h.
Then cooled to 25 C and poured into ice H2O (10 mL), the solution was basified with NH3 .H20 and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-TLC
(DCM/Me0H = 25/1) to give 7-bromo-6-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (80 mg, yield: 23.6%) as a yellow solid. ESI-MS [M+H]+: 243Ø
[0617] Synthesis of N-((7-bromo-6-fluoroimidazo11,5-alpyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide. To a mixture of 7-bromo-6-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (50 mg, 0.2 mmol), 2-methylpropane-2-sulfinamide (30 mg, 0.24 mmol) in dry THF (3 mL) was added Ti(0E04 (137 mg, 0.6 mmol). The mixture was stirred at 80 C for 16 h.
Water (20 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give N-((7-bromo-6-
309 fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide, which was used in the next step without further purification. (71.4 mg, crude). ESI-MS [M+H]+:
346.2 [0618] Synthesis of N-((7-bromo-6-fluoroimidazo11,5-alpyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide. To a mixture of N-((7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide (71.4 mg, crude from last step) in dry THF (3 mL) was added NaBH4 (30 mg, 0.8 mmol). The mixture was stirred at 25 C for 3 h. Then H20 (10 mL) was added, extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product which was purified by Prep-TLC (DCM/Me0H = 10/1) to give N-((7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (60 mg, yield: 85% over 2 steps) as a yellow oh. ESI-MS [M+H]+: 348.1 [0619] Synthesis of (7-bromo-6-fluoroimidazo[1,5-alpyridin-1-yl)methanamine. A
mixture of N4(7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (60 mg, 0.17 mmol) in TFA (2 mL) was stirred at RT for 16 h. Then concentrated to give (7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (39 mg, crude) as a yellow solid which was used in the next step without further purification. ESI-MS [M+H]:
227Ø
[0620] Synthesis of N-((7-bromo-6-fluoroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (I-151). To a mixture of 1((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (20 mg, 0.071 mmol), (7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (17.2 mg, 0.071 mmol), HOBT (19 mg, 0.14 mmol), EDCI (27 mg, 0.14 mmol) in DMF (3 mL) was added DIPEA (46 mg, 0.36 mmol). The mixture was stirred at 25 C for 3 h. Water (20 mL) was added and the mixture was extracted with Et0Ac (30 mL x 3). The combined organic layers was concentrated and purified by Prep-TLC (DCM/Me0H = 10/1) to give N47-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (18.9 mg, yield: 53%) as a yellow solid. ESI-MS
[M+H]: 507.9.
Purity: 94.07(214nm), 96.76 (254nm). 111NMR (400 MHz, DMSO-D6) 6 8.65-8.59(m, 2H), 8.33-8.29 (m, 2H), 8.20-8.16 (m, 2H), 7.85 (s, 1H), 7.72 (s, 1H), 7.39 (d, J =
9.3 Hz, 1H), 6.99 (dd, J = 9.3, 1.4 Hz, 1H), 5.38 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 1.95-1.88 (m, 1H), 0.92-0.89 (m, 2H), 0.68-0.65 (m, 2H).
310 Example 152 Scheme 151 o' ,vc N
rI) 0 ey-/ HN-N Li0H, THF, H20 N ______________________________________________________________ )1.
Cs2CO3, DMF, 50 C 40 C
OLi Cl HCI N%\
N-N
ve_ciN N-N
NN
HOBT, EDCI, DIPEA, DMF, 40 C 1-152 0 CI
[0621] Synthesis of methyl 1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1H-1,2,4-triazole-3-carboxylate. A mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (207 mg, 1.0 mmol), methyl 1H-1,2,4-triazole-3-carboxylate (190 mg, 1.5 mmol) and Cs2CO3 (1.6 g, 5 mmol) in DMF (8 mL) was stirred at 50 for 2 h. H20 (50 mL) was added to the reaction, then extracted with Et0Ac (50 mL x 2). The combined organic layers were concentrated, and purified by flash silica gel column(CH2C12/Me0H = 15/1) to give methyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate (130 mg, yield: 44%) as a white solid. ESI-MS [M+H]+: 298.1.
[0622] Synthesis of lithium 1-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-111-1,2,4-triazole-3-carboxylate. To a solution of methyl 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate (57 mg, 0.19 mmol) in THF/Et0H/H20(1 mL/1 mL/0.5 mL) was added LiOH (16 mg, 0.38 mmol). The mixture was stirred at 40 C
for 1 h.
Then concentrated and lyophilized to give lithium 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate (75 mg, crude) as a yellow solid.
ESI-MS [M+H]+:
284.1.
[0623] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-1,2,4-triazole-3-carboxamide (1-152). A
311 mixture of lithium 146-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate (75 mg, crude), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (41 mg, 0.19 mmol), HOBT (52 mg, 0.38 mmol), EDCI (73 mg, 0.38 mmol) and DIPEA
(123 mg, 0.95 mmol) in DMF (2.5 mL) was stirred at 40 C for 26 h. Water (10 mL) was added and extracted with Et0Ac (30 mL x 2), the combined organic layers were washed with brine, concentrated, the crude was purified by flash silica gel column (CH2C12/Me0H =
5/1) to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,4-triazole-3-carboxamide (27.9 mg, yield: 32%) as a yellow solid. ESI-MS
[M+H]+: 447.1. Purity: 99.48% (214 nm), 100% (254 nm). 111NMR (400 MHz, DMSO-d6) 6 8.83 (t, J = 5.1 Hz, 1H), 8.72 (s, 1H), 8.34-8.29 (m, 3H), 7.83-7.79 (m, 2H), 7.38 (d, J = 9.3 Hz, 1H), 7.00 (d, J = 9.1 Hz, 1H), 6.64 (d, J = 6.8 Hz, 1H), 5.54 (s, 2H), 4.60 (d, J = 5.6 Hz, 2H), 1.95-1.88 (m, 1H), 0.96-0.85 (m, 2H), 0.70-0.61 (m, 2H).
Example 153 Scheme 152 OH N
N: DMF HO
% HO
RT, 3 h NT) CuSO4, sodium ascorbate N
N3 t_BuOH/H20, RT, 3 h 0 NH, OH
Li0H, THF/Et0H H
\N
N11,-) \N
50 C, 3 h HATU, DIPFA N1/õ
DMFNOH , RT, 14 h CI

[0624]
Synthesis of ethyl 1-((6-cyclopropy1-8-(3-hydroxyoxetan-3-y1)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. A mixture of 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (500 mg, 1.8 mmol) and NaN3 (176 mg, 2.7 mmol) in DMF (15 mL) was stirred at RT for 3 h. H20 (30 mL) was added to the reaction, extracted with Et0Ac (50 mL x 3). The combined organic layers were washed brine, dried over Na2SO4, concentrate in vauo to give the crude product, which was purified with silica gel
312 chromatography (EA/PE = 1/1) to give the 3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (420 mg, yield: 82%) as a yellow solid. ESI-MS
[M+H]: 286.1 [0625] Synthesis of ethyl 1-08-(3-hydroxyoxetan-3-yl)imidazo 11,2-al pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of 3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (420 mg, 1.47 mmol) in t-BuOH/H20 (10 mL/10 mL) was added ethyl propiolate (158 mg, 1.6 mmol), CuSO4 (70 mg, 0.44 mmol) and sodium ascorbate (87 mg, 0.44 mmol). The resulting reaction was stirred at RT
for 3 h. The reaction was concentrated in vauco to give the residue, which was purified with silica gel chromatography (EA/PE = 1/1) to give the ethyl 148-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (400 mg, yield: 71%) as a yellow solid.
ESI-MS [M+H]: 383.2 [0626] Synthesis of 1-08-(3-hydroxyoxetan-3-yl)imidazo 11,2-al pyridin-2-yl)methyl)-111-1,2,3-triazole-4-carboxylic acid. A mixture of ethyl 148-(3-hydroxyoxetan-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (400 mg, 1.05 mmol) and LiOH (140 mg, 5.8 mmol) in THF/H20 (15 mL/5 mL) was stirred at 50 C for 3 h.
The reaction was concentrate in vacuo to give crude product, which was purified with Prep-HPLC to give 1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (220 mg, yield: 58%) as a yellow solid. ESI-MS [M+H]: 356.2 [0627] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-46-cyclopropyl-8-(3-hydroxyoxetan-3-y1)imidazo11,2-a]pyridin-2-y1)methyl)-111-1,2,3-triazole-4-carboxamide (1-153). To a solution of 148-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 0.28 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (87 mg, 0.4 mmol), HATU (177 mg, 0.47 mmol) in DMF (5 mL) was added DIPEA (200 mg, 1.55 mmol). The resulting mixture was stirred at RT
for 14 h. H20 (30 mL) was added into the reaction, extracted with EtOAC (50 mL
x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product, which was purified with Prep-TLC (DCM/Me0H = 10/1) to give the N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(3-hydroxyoxetan-3-y1)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxamide (30 mg, yield: 20%) as off white solid. ESI-MS [M+H]: 518.9. Purity: 94.5(214nm), 93.5(254nm). 1-HNMR
(400 MHz,
313 DMSO-d6) 6 8.92 (t, J = 5.9 Hz, 1H), 8.56 (s, 1H), 8.34-8.28 (m, 3H), 7.85-7.82 (m, 1H), 7.79 (s, 1H), 7.07 (d, J = 1.4 Hz, 1H), 6.66-6.62 (m, 1H), 6.42 (s, 1H), 5.76 (s, 2H), 5.22 (d, J = 6.5 Hz, 2H), 4.62 (t, J = 6.8 Hz, 4H), 1.98-1.91 (m, 1H), 0.95-0.90 (m, 2H), 0.70-0.66 (m, 2H).
Example 154 Scheme 153 Br HCI CN
CN
\
/ 0 HOBT, EDCI N, N, DIPEA, DMF
RT, 48 h 1454 Br [0628] Synthesis of N-((7-bromo-8-fluoroimidazo[1,5-alpyridin-1-y1)methyl)-5-((8-cyano-6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (I-154). A mixture of lithium 54(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate (100 mg, 0.32 mmol), (7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (106 mg, 0.38 mmol), EDCI (123 mg, 0.64 mmol), HOBT (86 mg, 0.64 mmol) and DIPEA (206 mg, 1.6 mmol) in DMF (3 mL) was stirred at RT
for 48 h. The mixture was concentrated to remove DMF, diluted with DCM/Me0H (30 mL, 10/1 (v/v)) and washed with H20 (10 mL x 2). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (DCM/Me0H = 10/1) to give N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (25.4 mg, yield: 15%) as a yellow solid. ESI-MS [M+H]+:
535ØPurity: 96.4 (214nm), 96.4 (254nm). 111NMR (400 MHz, DMSO-d6) 6 9.64 (t, J = 5.4 Hz, 1H), 8.69 (s, 1H), 8.46 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 7.3 Hz, 1H), 8.00 (s, 1H), 7.77 (s, 1H), 6.89-6.78 (m, 1H), 4.69 (d, J = 5.4 Hz, 2H), 4.53 (s, 2H), 2.00-1.95 (m, 1H), 1.02-0.91 (m, 2H), 0.82-0.70 (m, 2H).
314 Example 155 Scheme 154 H CI
:õ.10 O6...
N OBn CI SOO, DCM \ CO. Pd(dppf)Cl2 Cs2 CO3.
DMF1,1'06n N'N,..3....1(0Bn TEA. Et01-1. 80 C. 16 h 'NH
Et0H \IV luene, 110 C. 16 h N")--\N
n 43"-e" Bn 1V.N
LIOH-H20. H20.
RI, 3 h N
HATU. DIPEA.
H N

\*.nc [0629] Synthesis of benzyl 1-((6-cyclopropy1-8-(hydroxymethyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. A mixture of (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (550 mg, 2.33 mmol), benzyl 1H-pyrazole-4-carboxylate (520 mg, 2.56 mmol) and Cs2CO3 (1.90 g, 5.83 mmol) in DMF (10 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by flash silica gel chromatography (DCM/Me0H = 15/1) to give benzyl 14(6-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (710 mg, yield: 75%) as a white solid. ESI-MS [M+H]+: 403.1 [0630]
Synthesis of benzyl 1-((8-(chloromethyl)-6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. To a solution of benzyl 146-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (200 mg, 0.50 mmol) in DCM (5 mL) was added SOC12 (0.5 mL) at 0 C and the mixture was stirred for 2 h.
The mixture was concentrated to give benzyl 14(8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (200 mg, crude) as a yellow solid. ESI-MS
[M+H]+: 421.1.
315 [0631] Synthesis of benzyl 1-06-cyclopropy1-8-(2-ethoxy-2-oxoethyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. A mixture of benzyl 148-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (200 mg, 0.48 mmol), Pd(dppf)C12 (40 mg, 0.048 mmol) and TEA (1.0 mL) in Et0H (6.0 mL) was stirred at 80 C under CO for 16 h. The mixture was concentrated and purified by Prep-TLC
(DCM/Me0H =
20/1) to give benzyl 146-cyclopropy1-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (170 mg, yield:77%) as a light yellow oil. ESI-MS
[M+H]+: 458.9.
[0632] Synthesis of benzyl 1-06-cyclopropy1-8-(2-hydraziny1-2-oxoethyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. A
mixture of benzyl 146-cyclopropy1-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-y1) methyl)-1H-pyrazole-4-carboxylate (100 mg, 0.22 mmol) and NH2NH21120 (0.5 mL) in Et0H
(6.0 mL) was stirred at RT for 16 h. The mixture was concentrated to give benzyl 146-cyclopropy1-8-(2-hydraziny1-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (100 mg, crude) as a white solid. ESI-MS [M+H]+: 445.1.
[0633] Synthesis of benzyl 1-08-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate. A
mixture of benzyl 146-cyclopropy1-8-(2-hydraziny1-2-oxoethyl)imidazo[1,2-a] pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (50 mg, crude from last step), AcOH (0.15 mL) and triethoxymethane (0.15 mL) in toluene (3.0 mL) was stirred at 110 C for 16 h. The mixture was concentrated and purified by Prep-TLC (DCM/Me0H = 10/1) to give benzyl 14841,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxylate (40 mg, yield:80%) as a yellow oil. ESI-MS [M+Hr: 455.1.
[0634] Synthesis of 1-08-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid. A solution of benzyl 14(841,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo [1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (20.0 mg, 0.044 mmol) and LiORH20 (9.3 mg, 0.22 mmol) in a mixed solvent of THF/Me0H/H20 (1 mL/1 mL/1 mL) was stirred at RT for 3 h. The pH value was adjusted to 3 by 1 M HC1 solution and the mixture was extracted with i-PrOH/DCM = 1/3 (30 mL
x 3). The combined organic layers were concentrated to give 14841,3,4-oxadiazol-2-yl)methyl)-6-
316 cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (10.0 mg, crude) as a yellow oil. This material was used directly in the next step without further purification. ESI-MS [M+H]+: 365.1.
[0635] Synthesis of 1-08-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo 11,2-alpyridin-2-yl)methyl)-N-((7-chloroimidazo [1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (1-157). A mixture of 1-((84(1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a] pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (10.0 mg, crude from last step), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (7.5 mg, 0.034 mmol), HATU (15.4 mg, 0.041 mmol) and DIPEA (10.5 mg, 0.081 mmol) in DMF (2 mL) was stirred at 20 C for 4 h. The mixture was concentrated and purified by Prep-HPLC to give 1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (2.5 mg, yield: 11 %) as a light yellow solid. ESI-MS [M+Hr: 528.1.Purity: 98.5 (214nm), 93.9 (254nm).
1HNMR (400 MHz, DMSO-d6) 6 9.10 (s, 1H), 8.58 (t, J = 5.6 Hz, 1H), 8.30 (d, J = 8.4 Hz, 3H), 8.17 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.69 (s, 1H), 7.00 (s, 1H), 6.65 (dd, J = 7.4, 2.0 Hz, 1H), 5.38 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 4.50 (s, 2H), 1.98-1.84 (m, 1H), 0.93-0.89 (m, 2H), 0.66-0.63 (m, 2H).
Example 156 Scheme 155 CI

N
OLi EDCI, HOBt, DIPEA
N¨N 0 ,\N DMF, RT, 16 h H
Ns [0636] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-alpyridin-1-y1)methyl)-5-((6-cyclopropylimidazo[1,2-blpyridazin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (1-156).
To a solution of lithium 54(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate (50 mg, 0.13 mmol, crude) in DMF (5 mL) was added EDCI (58 mg, 0.3 mmol), HOBT (40 mg, 0.3 mmol), DIPEA (65 mg, 0.5 mmol) and (7-chloro-8-
317 fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (59 mg, 0.25 mmol).
The reaction was stirred at RT for 16 h. The mixture was poured into H20, the solid formed, filtered and washed with H20 and Me0H to give N4(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-546-cyclopropylimidazo[1,2-b]pyridazin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (15 mg, yield: 25%) as a yellow solid. ESI-MS [M+H]: 467.1.Purity:
96.71%(214nm),96.91%(254nm).
111 NMR (400 MHz, DMSO-d6) 6 9.63 (t, J = 5.4 Hz, 1H), 8.45 (d, J = 2.2 Hz, 1H), 8.22 (d, J =
7.4 Hz, 1H), 8.14 (s, 1H), 7.91 (d, J = 9.4 Hz, 1H), 7.09 (d, J = 9.4 Hz, 1H), 6.78 (t, J = 6.9 Hz, 1H), 4.70 (d, J = 5.5 Hz, 2H), 4.47 (s, 2H), 2.21-2.13 (m, 1H), 1.10-1.03 (m, 2H), 1.00-0.93 (m, 2H).
Example 157 Scheme 156 HO HO
N NH, 0 Hh F ":..... I 0H DOm...õõ."..,,,,, , ,5 oc, :'1,,.... ,, NaRNDhMF
, N, CusSoOdi:mtBausOcoHr/bHaf i v_LX,r, OEI RI,3 It fltv.2,T
v,Cl& EtO0C
,,,..- __1,1 N., N-...i¨\N
ii, Pd/C
N., NJ \
NON.,eB" R[3 It _________________ N'N3...yoBn TEA, Et0H.
65 C, 3 11 .
N oBn Me0H, RI, 1211 EtO0C
CI
EtO0C
HOOC
v&N N't'NN
N'''\N
NaOH (aq) r (,/---\N
..,,, , 0H HOBT. EDRC[1,3DI,EA, DMF 4,sis¨i........ed , isl 1......\CH 0 I-157a I-157b N

[0637] Synthesis of (2-amino-5-cyclopropylpyridin-3-yl)methanol. To a mixture of ethyl 2-amino-5-cyclopropylnicotinate (7.4 g, 36 mmol) in THF (70 mL) was added LAH (2.3 g, 61 mmol) was stirred at 0 C. The mixture was stirred at 0 "C for 3 h under N2 atmosphere. The reaction was monitored by LCMS until the starting material consumed. The reaction was quenched with H20 (5 mL), NaOH (15% aq., 5 mL), H20 (15 mL), after the mixture was stirred for 10 min, the mixture was filtered through celite and concentrated to give a residue. Which was
318 diluted with H20 (100 mL) and extracted with Et0Ac (100 mL x 5). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product, which was purified with silica gel (eluent: Et0Ac/PE: 1/2 to 1/0) to give the (2-amino-5-cyclopropylpyridin-3-yl)methanol (5 g, yield: 84%) as a white solid. ESI-MS
[M+H]: 165.2.
[0638] Synthesis of (2-(chloromethyl)-6-cyclopropylimidazo11,2-alpyridin-y1)methanol. To a solution of (2-amino-5-cyclopropylpyridin-3-yl)methanol (5 g, 30 mmol) in DMF (30 mL) was added 1,3-dichloropropan-2-one(14.8 g, 117 mmol). The mixture was stirred at 95 C for 3 h. The reaction was monitored by LCMS until the starting material consumed. The reaction was quenched with saturated aqueous NaHCO3 until pH = 8 and extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude productõ which was purified with silica gel (eluent:
DCM/MeOH: 50/1 to 10/1) to give (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (4.7 g, yield: 66%) as a yellow solid. ESI-MS [M+H]: 237.1.
[0639] Synthesis of (2-(azidomethyl)-6-cyclopropylimidazo11,2-alpyridin-8-y1)methanol. To a solution of (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (4.7 g, 20 mmol) in DMF (30 mL)was added sodium azide (1.82 g, 28 mmol). The mixture was stirred at RT for 3 h. The reaction was monitored by LCMS until the starting material consumed. The reaction was quenched with H20 (100 mL) and extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude productõ which was purified with silica gel (eluent:
DCM/MeOH: 50/1 to 10/1) to give (2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (2.1 g, yield: 43%) as a white solid. ESI-MS [M+H]: 244.2.
[0640] Synthesis of benzyl 1((6-cyclopropy1-8-(hydroxymethyl)imidazo 11,2-alpyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of (2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (2.1 g, 8.6 mmol) benzyl propiolate (2.1 g, 13 mmol), sodium ascorbate (1.7 g, 8.6 mmol) ,CuSO4 (1.4 g, 8.6 mmol) in tBuOH/H20 (20 mL/20 mL) was stirred at RT for 3 h. The reaction was quenched with H20 (50 mL) and extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product, which was purified with silica gel (eluent:
DCM/MeOH: 50/1 to 10/1) to give benzyl 1-((6-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-
319 alpyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.4 g, yield: 40%) as a white solid. ESI-MS [M+H]+: 404.2.
[0641] Synthesis of benzyl 1-08-(chloromethyl)-6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-111-1,2,3-triazole-4-carboxylate. To a mixture of benzyl 146-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.4 g, 3.5 mmol) in DCM (15 mL) was added SOC12 (5 mL). The mixture was stirred at RT for 3 h. The reaction was concentrated in vacuo to give the crude of benzyl 148-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.43 g, crude) as a yellow solid. ESI-MS [M+H]+: 422.1.
[0642] Synthesis of benzyl 1-06-cyclopropy1-8-(2-ethoxy-2-oxoethyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxylate. To a mixture of benzyl (chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.4 g, 3.4 mmol) in Et0H (15 mL) was added Pd(dppf)2C12 (38 mg, 0.34 mmol) and TEA (1.7 g, 17 mmol), the mixture was stirred at 65 C for 3 h under CO
atmosphere. The reaction was concentrated in vacuo to give the crude product, which was purified with silica gel (eluent: DCM/MeOH: 50/1 to 10/1) to give benzyl 146-cyclopropy1-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.1 g, yield: 70%) as a white solid. ESI-MS [M+H]+: 460.1.
[0643] Synthesis of 1-06-cyclopropy1-8-(2-ethoxy-2-oxoethyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxylic acid. To a mixture of benzyl 146-cyclopropy1-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.1 g, 2.4 mmol) in Me0H (20 mL) was added Pd/C (10%, 200 mg). The mixture was stirred at RT
under H2 atmosphere for 12 h. The reaction was filtered and washed with methanol, the filtrate was concentrated in vacuo to give the 146-cyclopropy1-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (600 mg, yield:
67%) as a yellow solid. ESI-MS [M+H]+: 370.2.
[0644] Synthesis of ethyl 2-(2-04-0(7-chloro-8-fluoroimidazo11,5-alpyridin-1-y1)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo11,2-a]pyridin-8-y1)acetate (I-157a). To a mixture of 146-cyclopropy1-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (300 mg, 0.81 mmol) in DIVIF (5 mL)
320 was added (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine HCl salt (228 mg, 0.97 mmol), HOBT(147 mg, 1.1 mmol), EDCI (211 mg, 1.1 mmol) and DIPEA (502 mg, 4 mmol).
The mixture was stirred at RT for 3 h. The reaction was quenched with H20 (30 mL) and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product, which was purified with silica gel (eluent: DCM/MeOH: 50/1 to 10/1) to give the ethyl 2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate (200 mg, yield: 45%) as a white solid. ESI-MS [M+H]+:
551.2. Purity:
96.2 (214nm), 95.9 (254nm). IENMR (400 MHz, DMSO-d6) 6 8.69 (t, J = 5.2 Hz, 1H), 8.51 (s, 1H), 8.45 (s, 1H), 8.28 (s, 1H), 8.21 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 6.96 (s, 1H), 6.76 (t, J = 6.7 Hz, 1H), 5.72 (s, 2H), 4.70 (d, J = 5.2 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.87 (s, 2H), 1.97-1.87 (m, 1H), 1.12 (t, J = 7.1 Hz, 3H), 0.98-0.88 (m, 2H), 0.70-0.62 (m, 2H).
[0645] Synthesis of 2-(24(4-0(7-chloro-8-fluoroimidazo[1,5-alpyridin-1-y1)methyl)carbamoy1)-111-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)acetic acid (I-157b). A mixture of ethyl 2-(24(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate (100 mg, 0.18 mmol) and NaOH (20 mg in 1 mL H20) in Et0H (20 mL) was stirred at RT for 3 h. The reaction was quenched with HC1 (1N, 1 mL). The resulting mixture was concentrated to give the crude which was purified by Prep-HPLC to give 2-(24(44(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoy1)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetic acid (18 mg, 19% yield) as a white solid. ESI-MS
[M+H]+: 523ØPurity: 91.0 (214nm), 94.5 (254nm). 1H NIVIR (400 MHz, DMSO-d6) 6 8.72 (t, J
= 4.8 Hz, 1H), 8.53 (s, 1H), 8.45 (s, 1H), 8.31-8.17 (m, 2H), 7.78 (s, 1H), 6.94 (s, 1H), 6.76 (t, J
= 6.9 Hz, 1H), 5.72 (s, 2H), 4.70 (d, J = 5.3 Hz, 2H), 3.75 (s, 2H), 1.95-1.86 (m, 1H), 0.95-0.85 (m, 2H), 0.67-0.62 (m, 2H).
321 Example 158 Scheme 157 CN ,var-N

H
HOBT, EDCI N
N ,N DIPEA, DMF \N
RT, 48 h I-158 0 F
CI
[0646] Synthesis of N4(7-chloro-8-fluoroimidazo11,5-alpyridin-1-y1)methyl)-5-((8-cyano-6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide. A
mixture of lithium 548-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate (100 mg, 0.32 mmol), (7-chloro-8-fluoroimidazo[1,5-a]
pyridin-l-yl)methanamine (113 mg, 0.48 mmol), EDCI (123 mg, 0.64 mmol), HOBT (86 mg, 0.64 mmol) and DIPEA (206 mg, 1.6 mmol) in DIVIF (3 mL) was stirred at RT for 48 h. The mixture was concentrated to remove DIVIF, diluted with DCM/Me0H (30 mL, 10/1 (v/v)) and washed with H20 (20 mL x 2). The organic layers were separated, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (DCM/Me0H
= 10/1) to give N47-chloro-8-fluoroimidazo[1,5-a] pyridin-1-yl)methyl)-548-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1,3,4-oxadiazole-2-carboxamide (20 mg, yield:
13%) as a yellow solid. ESI-MS [M+H]+: 490.9.Purity: 99.0 (214nm), 98.6 (254nm). 11-1NMR
(400 MHz, DMSO-d6) 6 9.65 (t, J = 5.4 Hz, 1H), 8.69 (d, J = 1.3 Hz, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 7.4 Hz, 1H), 8.00 (s, 1H), 7.78 (d, J = 1.6 Hz, 1H), 6.83-6.73 (m, 1H), 4.70 (d, J
= 5.5 Hz, 2H), 4.53 (s, 2H), 2.02-1.95 (m, 1H), 1.02-0.89 (m, 2H), 0.78-0.74 (m, 2H).
322 Example 159 Scheme 158 /OH
[j¨ B
OH

N NH, - -NaOH, L-Proline IN NH, N NH, NBS Pd(0A02, PCY3,K3PO4 I / _____ Br Cul, DMSO, 160 C CH3CN Br1S0 dioxane, H20, I00 C, 16 h S, N 1/1\1 0=S=0 NH CI 0 CI N
DMF, 90 C K2CO3, DMF, 60 C .. N N

[0647] Synthesis of 3-(methylsulfonyl)pyridin-2-amine. To a solution of 3-bromopyridin-2-amine (2 g, 11.5 mmol) in DMSO (20 mL) was added sodium methanesulfonate (1.534 g, 15 mmol), L-Proline (266 mg, 2.31 mmol), CuI (220 mg, 1.16 mmol) and NaOH (92 mg, 2.31 mmol). The reaction mixture was degassed with nitrogen for 2 min and irradiated in microwave at 160 C for 40 min, and subsequently quenched with H20 (30 mL), extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (PE/Et0Ac = 2/1) to give the 3-(methylsulfonyl)pyridin-2-amine as a yellow solid (843 mg, yield: 42%). ESI-MS
[M+H]+:
173.1.
[0648] Synthesis of ethyl 5-bromo-3-(methylsulfonyl)pyridin-2-amine. To a solution 3-(methylsulfonyl)pyridin-2-amine (843 mg, 4.9 mmol) in CH3CN (20 mL) was added NB S (915 mg, 5.14 mmol) at RT. The resulting mixture was stirred at RT for 0.5 h and subsequently concentrated to give the residue, which was diluted with H20 (50 mL) and extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product, which was purified by silica gel chromatography (PE/Et0Ac = 1/1) to give 5-bromo-3-(methylsulfonyl)pyridin-2-amine (1.161 g, yield: 94%) as a yellow solid. ESI-MS [M+H]+: 250.9
323 [0649] Synthesis of 5-cyclopropy1-3-(methylsulfonyl)pyridin-2-amine. To a solution of 5-bromo-3-(methylsulfonyl)pyridin-2-amine (1.16 g, 4.62 mmol) in dioxane/H20 (50 mL/50 mL) was added cyclopropylboronic acid (794 mg, 9.25 mmol), Pd(OAc)2 (104 mg, 0.46 mmol), PCy3 (259 mg, 0.925 mmol) and K3PO4 (1.963 g, 9.25 mmol). The reaction mixture was stirred at 100 C for 14 h under nitrogen. Then the mixture was concentrated in vacuo.
Water (100 mL) was added and the mixture was extracted with Et0Ac (100 mL x 3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (PE/Et0Ac = 1/1) to give the 5-cyclopropy1-3-(methylsulfonyl)pyridin-2-amine as a yellow solid (619 mg, yield: 63%). ESI-MS [M+H]+: 213.1.
[0650] Synthesis of 2-(chloromethyl)-6-cyclopropy1-8-(methylsulfony1)-3,8a-dihydroimidazo[1,2-al pyridine. To a solution of 5-cyclopropy1-3-(methylsulfonyl)pyridin-2-amine (102 mg, 0.45 mmol) and 1,3-dichloropropan-2-one(183 mg,1.44 mmol) in Et0Ac (10 mL) .The reaction mixture was stirred at 90 C for 20 h. Then H20 (30 mL) was added and extracted with Et0Ac (50 mL x 3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (PE/Et0Ac =
2/1) to give 2-(chloromethyl)-6-cyclopropy1-8-(methylsulfony1)-3,8a-dihydroimidazo[1,2-a]pyridine (97 mg, yield: 75%) as a yellow solid. ESI-MS [M+H]: 285Ø
[0651] Synthesis of N-((7-chloroimidazo11,5-alpyridin-1-yl)methyl)-1-46-cyclopropyl-8-(methylsulfonyl)imidazo11,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (1-159). To a solution of 2-(chloromethyl)-6-cyclopropy1-8-(methylsulfonyl)imidazo[1,2-a]pyridine (97 mg, 0.34 mmol), N4(7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (94 mg, 0.68 mmol) and K2CO3(94 mg, 0.68 mmol) in DMF (10 mL). The resulting mixture was stirred for overnight at 60 C. The mixture was concentrated to remove solvent to give the crude product, which was purified by prep-HPLC to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(methylsulfonyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (40 mg, yield:
23%) as a light yellow solid. ESI-MS [M+H]: 523.9.Purity: 96.55% (214 nm), 95.34% (254 nm). 1HNMR (400 MHz, Me0D) 6 9.07 (s, 1H), 8.54 (s, 1H), 8.36 (d, J = 7.6 Hz, 1H), 8.24 (s, 1H), 7.98 (s, 1H), 7.92 (s, 2H), 7.81 (s, 1H), 7.00 (d, J = 2.0 Hz, 1H), 5.56 (s, 2H), 4.80 (s, 2H), 3.40 (s, 3H), 2.11-2.03 (m, 1H), 1.11-1.03 (m, 2H), 0.81-0.76 (m, 2H).
324 Example 160 Scheme 159 co HN-NH2 H2SO4 NN. 0H HN-N 0¨

) NH 0 I .4-clioxane/AcOH (I:1) K2CO2, RT. overnight).- H2N T313. DIPEA. I
.4-dicotane, I 00 C, 2 h N =
0 RT.4 h NN N
N N
HCI _tar Li0H-1-1,0 H2N CI
¨N
THE, Et0H. H20 0H 13P, DIPEA. iPrOH, RT. 2 h N
30 C, 2 h 1-160 [0652] Synthesis of methyl 2-amino-2-(2-methylhydrazono)acetate. A
mixture of methylhydrazine sulfate (360 mg, 2.5 mmol) and K2CO3 (690 mg, 5.0 mmol) in ethanol (10 mL) was stirred at RT for 10 minutes, and then ethyl 2-amino-2-thioxoacetate (333 mg, 2.5 mmol) was added at 0 C. The mixture was stirred at RT overnight and filtered. The filtrate was concentrated and purified by Prep-TLC (DCM/Me0H = 15:1) to give methyl 2-amino-2-(2-methylhydrazono)acetate (180 mg, yield: 55%) as a yellow solid. ESI-MS [M+H]+:
132.2 [0653] Synthesis of methyl 2-(2-(6-cyclopropylimidazo11,2-alpyridin-2-yl)acetamido)-2-(2-methylhydrazono)acetate. A solution of methyl 2-amino-2-(2-methylhydrazono)acetate (52 mg, 0.4 mmol), 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetic acid (86.4 mg, 0.4 mmol) in 1,4-dioxane (6 mL) was stirred at RT for 10 minutes, and then T3P
(50 wt.% in EA, 524 mg, 0.8 mmol) and DIPEA (100 mg, 0.8 mmol) were added.
After the mixture was stirred at RT for 1.5 h, solvent was concentrated and the crude product was used into the next step without further purification. ESI-MS [M+H]: 330.2.
[0654] Synthesis of methyl 5-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1-methyl-111-1,2,4-triazole-3-carboxylate. A solution of methyl 2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetamido)-2-(2-methylhydrazono)acetate (crude from last step) in AcOH/1,4-dioxane (1:1, 5 mL) was stirred at 100 C for 2 h. Water (20 mL) was added and the mixture was extracted with Et0Ac (50 mL*3). The combined organic layers were concentrated and purified by Prep-TLC (DCM:Me0H = 15:1) to give methyl 546-cyclopropylimidazo[1,2-a]pyridin-2-
325 yl)methyl)-1-methyl-1H-1,2,4-triazole-3-carboxylate (60 mg, yield: 48% over 2 steps) as a white solid. ESI-MS [M+H]+: 312.2.
[0655] Synthesis of 5-((6-cyclopropylimidazo11,2-alpyridin-2-y1)methyl)-1-methyl-111-1,2,4-triazole-3-carboxylic acid. To a solution of methyl 546-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-1,2,4-triazole-3-carboxylate (50 mg, 0.16 mmol) in ethanol (3 mL)/THF (3 mL)/H20 (1.5 mL) was added LiOEIH20 (16 mg, 0.39 mmol). The mixture was stirred at 30 C for 2 h. The mixture was concentrated and the crude product (60 mg, crude) was used into the next step without further purification. ESI-MS [M+H]+: 298.2.
[0656] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1-methyl-111-1,2,4-triazole-3-carboxamide.
A mixture of 546-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-1,2,4-triazole-3-carboxylic acid (60 mg, crude from last step), (7-chloroimidazo[1,5-a]pyridin-l-yl)methanamine hydrochloride (41 mg, 0.19 mmol), and DIPEA (101 mg, 0.785 mmol) in isopropanol (6 mL) was stirred at RT for 10 minutes. T3P (50 wt.% in EA, 250 mg, 0.39 mmol) was added. The mixture was stirred at RT overnight. Water (10 mL) was added and extracted with Et0Ac (30 mL*3). The combined organic layers were concentrated and purified by Prep-HPLC to give N47-chloroimidazo[1,5-a]pyridin-l-yl)methyl)-546-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1-methyl-1H-1,2,4-triazole-3-carboxamide (7.3 mg, yield: 10% over 2 steps) as a yellow solid. ESI-MS [M+H]+: 461.1. Purity: 98.14 (214 nm), 98.24 (254 nm). 111 NMR (400 MHz, DMSO-d6) 6 8.70 (t, J = 5.9 Hz, 1H), 8.28-8.25 (m, 3H), 7.81 (s, 1H), 7.64 (s, 1H), 7.32 (d, J = 9.3 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 6.61 (dd, J = 7.4, 1.8 Hz, 1H), 4.56 (d, J =
5.9 Hz, 2H), 4.25 (s, 2H), 3.86 (s, 3H), 1.91-1.85 (m, 1H), 0.90-0.85 (m, 2H), 0.64-0.61 (m, 2H).
326 Example 161 Scheme 160 NH
( 0 0 NH 2 "*--NO)Hr N 0 0 NH2NH2c:FI:Og. Et0H ,.... ,..., Nfki¨N'H

EtOH, 30 C, 72 ______________________________________________ ).-(____r tl,NIN micro:. 160 C
h N --_,----(1 H2 xylene, 2 h N -'N N
a ..... __IX
Nfh__ CI võ. ===,, .01.1¨__ LIOH=H20 -,õ N....h._ H2N N ----:\
Nslekõf0,--õ, I HE, EtOH, H20 NsN11,,OH I313, DIPEA, iPrOH, CI
[0657] Synthesis of 2-(6-cyclopropylimidazo11,2-a] pyridin-2-yl)acetohydrazide. A
mixture of ethyl 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate (650 mg, 2.66 mmol) and hydrazine hydrate (2.0 mL) in ethanol (8 mL) was stirred at 80 C overnight.
The mixture was concentrated and purified by silica gel chromatography (DCM/Me0H = 5:1) to give 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide (240 mg, yield: 39%) as a white solid.
ESI-MS [M+H]: 231.1 [0658] Synthesis of ethyl 2-amino-2-(2-(2-(6-cyclopropylimidazo11,2-a]
pyridin-2-yl)acetyl)hydrazono)acetate. A solution of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide (115 mg, 0.5 mmol) and ethyl 2-ethoxy-2-iminoacetate (145 mg, 1.0 mmol) in ethanol (2.0 mL) was stirred at RT for 3 days. The mixture was concentrated to get a yellow solid (165 mg, crude) which was used into the next step without further purification. ESI-MS
[M+I-I]+: 330.1.
[0659] Synthesis of ethyl 54(6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-411-1,2,4-triazole-3-carboxylate. A solution of ethyl 2-amino-2-(2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl)hydrazono)acetate (165 mg, crude from last step) in xylene (4.0 mL) was stirred at 160 C under microwave irradiation for 3 h. The mixture was concentrated and purified by Prep-TLC (DCM/Me0H = 5:1) to give ethyl 5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4H-1,2,4-triazole-3-carboxylate (100 mg, yield: 64% over 2 steps) as a yellow solid.
ESI-MS [M+H]: 312.1.
[0660] Synthesis of 54(6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-411-1,2,4-triazole-3-carboxylic acid. To a solution of ethyl 546-cyclopropylimidazo[1,2-a]pyridin-2-
327 yl)methyl)-4H-1,2,4-triazole-3-carboxylate (50 mg, 0.16 mmol) in ethanol (3 mL)/THF (3 mL)/H20 (0.5 mL) was added LiORH20 (13.5 mg, 0.32 mmol). After the mixture was stirred at RT overnight, solvent was concentrated and the crude (60 mg) was used into the next step without further purification. ESI-MS [M+H]+: 284.2.
[0661] Synthesis of N-((7-chloroimidazo[1,5-a1pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-411-1,2,4-triazole-3-carboxamide (I-161). A
solution of crude 54(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4H-1,2,4-triazole-3-carboxylic acid (60 mg, crude from last step), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (35 mg, 0.16 mmol), and DIPEA (83 mg, 0.64 mmol) in isopropanol (6 mL) was stirred at RT for 10 minutes. And then T3P (50 wt.% in EA, 204 mg, 0.32 mmol) was added. The mixture was stirred at RT overnight, H20 (15 mL) was added and extracted with DCM and Me0H (10:1, 50 mL*3). The combined organic layers were concentrated and purified by Prep-HPLC to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-4H-1,2,4-triazole-3-carboxamide (13.1 mg, yield: 18%
over 2 steps) as a white solid. ESI-MS [M+H]+: 447.2. Purity: 95.13 (214 nm), 96.02 (254 nm). 1H
NMR (400 MHz, DMSO-d6) 6 8.83 (s, 1H), 8.24-8.22 (m, 3H), 7.79 (s, 1H), 7.55 (s, 1H), 7.27 (d, J = 9.3 Hz, 1H), 6.88 (d, J = 9.3 Hz, 1H), 6.58 (dd, J = 7.4, 1.8 Hz, 1H), 4.54 (d, J
= 5.9 Hz, 2H), 4.09 (s, 2H), 1.87-1.81 (m, 1H), 0.85-0.82 (m, 2H), 0.61-0.57 (m, 2H).
Example 162 Scheme 161 CI
CI

OH
B"-'0)---ri Pd/C H2 HO)L0 H
MeOLL RI 2 h EDDCm'I H205BoTc: Di6IPhEA
a 0 r a SOCl2. DCM \ ......"')..õ,,, KC, N..... ,..,. I) LDA. -40 C)'T h 2)-78 C, 2 h 1-162 \-----N ..-"
328 [0662] Synthesis of 1-06-cyclopropy1-8-(hydroxymethyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxylic acid. The mixture of benzyl 146-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (260 mg, 0.646 mmol) and Pd/C (100 mg) in Me0H (6 mL) and THF (3 mL) was stirred at RT for 2 h under H2 (balloon). The reaction mixture was filtered and the filtrate was concentrated and dried in vacuo to give 146-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (180 mg, yield: 89%) as a yellow solid. ESI-MS [M+H]+: 313Ø
[0663] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-46-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide. The mixture of 146-cyclopropy1-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (180 mg, 0.576 mmol), (5-chloro-2-(1H-tetrazol-5-yl)phenyl)methanamine (188 mg, 0.864 mmol), EDCI (133 mg, 0.691 mmol), HOBT
(93 mg, 0.691 mmol) and DIPEA (223 mg, 1.728 mmol) in DMF (6 mL) was stirred at 25 C
for 16 h.
The reaction mixture was poured into H20 (60 mL) and the precipitate was collected, dried in vacuo to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (200 mg, yield: 73%) as a pale white solid. ESI-MS [M+H]+: 475.9.
[0664] Synthesis of N-((7-chloroimidazo[1,5-alpyridin-1-yl)methyl)-1-48-(chloromethyl)-6-cyclopropylimidazo[1,2-alpyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide. To a stirred solution of N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-146-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (180 mg, 0.378 mmol) in DCM (10 mL) and THF (4 mL) was added dropwise of S0C12 (450 mg, 3.78 mmol) at 0 C. The mixture was stirred at RT for 1 h. The reaction mixture was concentrated. The residue was dissolved in Et0Ac (30 mL) and washed with NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, concentrated and dried in vacuo to give N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-148-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-4-carboxamide (150 mg, crude) as a yellow solid. ESI-MS
[M+H]+: 494Ø
[0665] Synthesis of ethyl 3-(24(4-(((7-chloroimidazo 11,5-al pyridin-1-yl)methyl)carbamoy1)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-al pyridin-8-y1)-
329 2,2-dimethylpropanoate (1-162). To a stirred solution of ethyl isobutyrate (0.53 g, 4.5 mmol) in THF (6 mL) was added LDA (2.4 mL, 2 M in THF) at -40 C under N2. After 1 h, the solution above was added dropwise to the suspension of N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-148-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-y1)methyl)-1H-pyrazole-carboxamide (150 mg, crude from last step) in THF (10 mL) at -78 C. The resulting mixture was stirred for 2 h at -78 C. The reaction mixture was quenched with saturated aqueous NH4C1 (30 mL), then adjusted the pH to 9-10 by NaHCO3 aqueous, extracted with Et0Ac/THF (50 mL
x 3). The combined organics were washed with brine, dried over Na2SO4, concentrated and purified by Prep-TLC (DCM/Me0H = 8/1) to give ethyl 3-(2444(7-chloroimidazo[1,5-a]pyridin-1-y1)methyl)carbamoy1)-1H-pyrazol-1-y1)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-y1)-2,2-dimethylpropanoate (10 mg, yield: 5%) as a white solid. ESI-MS
[M+H]+: 574.1.
Purity: 96.55 (214nm), 95.05 (254nm). 1H NIVIR (400 MHz, DMSO-d6) 6 8.55 (t, J
= 5.5 Hz, 1H), 8.33-8.28 (m, 2H), 8.20 (s, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 6.70-6.62 (m, 2H), 5.37 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 3.95 (q, J = 7.1 Hz, 2H), 3.09 (s, 2H), 1.91-1.83 (m, 1H), 1.24-1.07 (m, 9H), 0.93-0.86 (m, 2H), 0.62 -0.57 (m, 2H).
330 Example 163 Scheme 162 N NH2 0 /¨ 0 NH2 Pd/C

_ ______ Arr-)Li 0 ,õ.., ¨/
IN
MeCN, RT =VU Br ________________________ ss I Et0H, RT
Pd(OAc)2, PPh3 N NH2 TEA, 95 C

r õpovir0 0 ....v,g0 0 0,- 0 cic, ,)--0Bn NaN3, DMF /
AIL DMF, 95 C, 12 h .---- --N\ /CI ________________ RT, 2 h ).-.,...- .e...N N3 CuSO4, sodium ascorbate N NH2 N,, / t-BuOH/H20, RT, 2 h '..., NI...) r r ........... jy___ CI HCI
...--- ---N
Pd/C, Et0H J- ....,N =:::,...,.N.-..,%
RT, 13 h =-=... NI.)¨\N EDCI, HOBt, DIPEA
N( OH DMF, RT, 16 h N

r vIOH

v.. \
Li0H, Et0H/H N"
20 N....)¨\N
NI-) N N %-"\ _____ NraN Iit\II RT, 2 h N
N
I-163a 0 I-163b 0 F CI
F CI
[0666] Synthesis of 3-bromo-5-cyclopropylpyridin-2-amine. A mixture of 5-cyclopropylpyridin-2-amine (10 g, 74.5 mmol) in MeCN (130 mL) was added 1-Bromo-2, 5-pyrrolidinedione (16 g, 89.4 mmol) at RT. The mixture was stirred for 3 h. The mixture was concentrated, diluted with H20 (200 mL) and exacted by Et0Ac (200 mL x 3) and H20 (250 mL). The combined organic phases were concentrated to give 3-bromo-5-cyclopropylpyridin-2-amine (15.0 g, crude) as a yellow solid. ESI-MS [M+H]: 213.0
331 [0667] Synthesis of ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)acrylate.
To a solution of 3-bromo-5-cyclopropylpyridin-2-amine (7.00 g, 33 mmol) in DMF (60 mL) was added TEA (15 mL), PPh3 (1.74 g, 16.43 mmol), Pd(OAc)2 (0.75 g 3.3 mmol) and ethyl acrylate (6 mL, 65.7 mmol) at RT. The mixture was heated to 95 C and stirred for 16 h.
Water (70 mL) was added and the mixture were exacted by Et0Ac (100 mL x 3). The organic phases were concentrated to give ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)acrylate (4 g, yield: crude) as a yellow solid. ESI-MS [M+H]+: 233.1.
[0668] Synthesis of ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)propanoate. To a solution of ethyl (E)-3-(2-amino-5-cyclopropylpyridin-3-yl)acrylate (4 g, crude from last step) in Et0H(50 mL)/Et0Ac() (10 mL) was added Pd/C (400 mg) at RT. The mixture was stirred for 16 h. The mixture were filtered and concentrated to give ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)propanoate (4 g, crude) as a yellow oil. ESI-MS [M+H]+: 235.1.
[0669] Synthesis of ethyl 3-(2-(chloromethyl)-6-cyclopropylimidazo11,2-alpyridin-8-y1)propanoate. To a solution of 3-(2-amino-5-cyclopropylpyridin-3-yl)propanoate (4 g, crude) in DMF (30 mL) was added 1,3-dichloropropan-2-one (11.7 g, 92 mmol) at RT. The mixture was heated to 95 C and stirred for 16 h. H20 (100 mL) was added to reaction, exacted by Et0Ac (100 mL x 3). The organic phases were concentrated and purified by flash silica gel chromatography (0-60% Et0Ac in PE) to give ethyl 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (2.2 g, yield: 22 % over 3 steps) as a red oil.
ESI-MS [M+H]: 307.1.
[0670] Synthesis of ethyl 3-(2-(azidomethyl)-6-cyclopropylimidazo11,2-alpyridin-8-y1)propanoate. To a solution of ethyl 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (2.2 g, 7.17 mmol) in DMF (30 mL) was added NaN3 (416 mg, 6.40 mmol) at RT. The mixture was stirred for 2 h. H20 (100 mL) was added to reaction, exacted by Et0Ac (100 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated to give ethyl 3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (1.6 g, crude) as a red oil. ESI-MS [M+H]: 314.1.
[0671] Synthesis of benzyl 1-06-cyclopropy1-8-(3-ethoxy-3-oxopropyl)imidazo11,2-alpyridin-2-y1)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of ethyl 3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (1.6 g, crude) in t-
332 DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME:
ii NOTE POUR LE TOME / VOLUME NOTE:

Claims (20)

WO 2019/178129 PCT/US2019/021897What is claimed is:
1. A compound of Formula (I):

N
R7 \
N N (I) R CyA CyB

R2 Rl or a pharmaceutically acceptable salt thereof, wherein:
CyA is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyenel having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyA
is substituted with 0-4 RA groups;
each RA is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
CyB is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with O-S RB groups;
each RB is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
L is selected from -QC(R)2-, -C(R)2Q-, -QC(Q)-, -C(Q)Q-, -C(R)2QC(0)-, and -C(0)QC(R)2-, wherein each Q is independently a monovalent or divalent group as valency allows, selected from the group consisting of 0, N(R), or (S);
RI-, R2, R3, and R4 are independently selected from hydrogen and C 1-6 aliphatic;
R5, R6, R7, R8, and R9 are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen, -CN, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;

or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur;
with the proviso that the compound is other than N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-243-chloroquinolin-6-yl)methyl)isonicotinamide.
2. The compound of claim 1, wherein the compound is of Formula (IV):

R"
L-CyA
$N
w4 R13 or a pharmaceutically acceptable salt thereof, wherein:
CyA is a 5-membered heteroarylene having 1-4 heteroatoms selected from oxygen or nitrogen, wherein CyA is substituted with 0-3 RA groups;
L is selected from -NC(0)- and -C(0)N-;
R6, R8, and R9 are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
R7 is -F, -C1, or -Br;
W4 is carbon or nitrogen;
Rm and R" are each optionally present, and if present are independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
R" is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C2-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
K is optionally present, and if present and is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C3-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
3. The compound of any one of the preceding claims, wherein the compound is of Formula (V):

L¨CyA
$N

Rio or a pharmaceutically acceptable salt thereof, wherein:
CyA is a 5-membered heteroarylene having 1-4 nitrogens, wherein when CyA
comprises 3 1\1-1\11 VIL'N\' I
nitrogens, CyA is not H=
L is selected from -NC(0)- and -C(0)N-;

R6, R8, and R9 are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
R7 is -F, -C1, or -Br;
Rm is optionally present, and if present is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
R" is optionally present, and if present is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
R" is selected from -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- or 5-7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;

K is optionally present, and if present and is selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C3.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
4. The compound of any one of the preceding claims, wherein L is selected from the group consisting of:
N(oek#

RN
kNI(\k, k N
wherein # represents to point of attachment to CyA.
5. The compound of any one of the preceding claims, wherein the compound is of Formula (II):
CyA CyB
(II) 0 R2 R.1 or a pharmaceutically acceptable salt thereof, wherein:
CyA is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyenel having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyA
is substituted with 0-4 RA groups;
each RA is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
CyB is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with O-S RB groups;
each RB is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
RI- and R2 are independently selected from hydrogen and C 1-6 aliphatic;
R6 and R7 are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen, -CN, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur;

with the proviso that the compound is other than N47-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-243-chloroquinolin-6-yl)methyl)isonicotinamide.
6. The compound of any one of the preceding claims, wherein CyA is selected from 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur wherein CyA is substituted with 0-4 RA groups.
7. The compound of any one of the preceding claims, wherein CyA is a 5-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyA is substituted with 0-2 RA groups.
8. The compound of any one of the preceding claims, wherein CyA is selected from the group consisting of:
N=N A vc r":"zi\i (R
* (RAh)-2 -1RA)0-1 N
N-N N-N
soRA)0_1 "
A N-NH
0_1- H
--'(RA (R)o-2 *
(RA)õ,--r H (RA o-f H

Nr--N vc R 1 p j A fro H. (no_e-c: H*( H*
s(RA)0_1 (RA H.
wherein * represents to point of attachment to L.
9. The compound of any one of the preceding claims, wherein the compound is of Formula (III-a) through (III-d):
NN
N

N,N
(RA)0-1 )(CY B (RA)13-1Ncy13 (III-a) (III-b) NN

N, Of/ --\() -1cCyB NCyB
R2 RI R,, (III-c) (III-d) or a pharmaceutically acceptable salt thereof, wherein:
each RA is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, S(0)2N(R)2, or an optionally substituted group selected from Ci.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
CyB is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with O-S RB groups;
each RB is independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
RI- and R2 are independently selected from hydrogen and C1.6 aliphatic;
R6 and R7 are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1.6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
10. The compound of any one of the preceding claims, wherein CyB is a 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyB is substituted with 0-5 RB groups.
11. The compound of any one of the preceding claims, wherein CyB is RI2 w3 I

Rio Ri4 wherein:
wl, w2, w3, and W4 are independently selected from carbon and nitrogen;
R10, R11, R12, K-13, and R14 are each optionally present when attached to a carbon atom, and if present correspond to an occurrence of RB independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
12. The compound of any one of the preceding claims, wherein CyB is selected from the group consisting of:
N
HN N
N N,N
h h II
Nr,) (RB)0-5 (RB)0-5 (RB)0-4 (RB)0-4 (RB)0-4 (RB)0-4 N N
Nj (R%-5 (RB)o-4
13. The compound of any one of the preceding claims, wherein CyB is RI2 w3 R

wherein:
W2 is selected from carbon, nitrogen, oxygen, and sulfur;
W3, and W4 are independently selected from carbon and nitrogen;
R10, R11, R12, K-13, and R14 are each optionally present when attached to a carbon atom, and if present correspond to an occurrence of RB independently selected from halogen, -CN, -C(R)=N(R), -C(0)R, -C(0)2R, -C(0)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(0)R, -N(R)C(0)2R, -N(R)C(0)N(R)2, -N(R)S(0)2R, -OR, -0C(0)R, -0C(0)N(R)2, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
and each R is independently hydrogen, -CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5-to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.
14. The compound of any one of the preceding claims, wherein CyB is selected from the group consisting of:

N)( (RB)o-5 (RB)o-5 (RB)o-4 (RB)o-4 (RB)o-4
15. The compound of any one of the preceding claims, wherein R5, R6, R7, R8, and R9 are independently selected from hydrogen, halogen, -CN, -N(R)2, -OR, or an optionally substituted group selected from C1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, wherein each R is independently hydrogen or C 1-6 aliphatic.
16. The compound of any one of the preceding claims, wherein R6 is selected from hydrogen or halogen.
17. The compound of any one of the preceding claims, wherein the compound is any one of compounds I-1 through 1-303 as shown in Table 1, or a pharmaceutically acceptable salt thereof
18. A pharmaceutical composition comprising any one of the preceding compounds further comprising a pharmaceutically acceptable excipient.
19. A method of treating a plasma kallikrein-mediated disease or disorder using a compound or composition of any one of the preceding claims.
20. A method of treating hereditary angioedema or diabetic macular edema comprising administering to a patient in need thereof a compound of any one of the preceding claims.
CA3093802A 2018-03-13 2019-03-12 Substituted imidazopyridines as inhibitors of plasma kallikrein and uses thereof Pending CA3093802A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201862642376P 2018-03-13 2018-03-13
US62/642,376 2018-03-13
US201862757728P 2018-11-08 2018-11-08
US62/757,728 2018-11-08
PCT/US2019/021897 WO2019178129A1 (en) 2018-03-13 2019-03-12 Substituted imidazopyridines as inhibitors of plasma kallikrein and uses thereof

Publications (1)

Publication Number Publication Date
CA3093802A1 true CA3093802A1 (en) 2019-09-19

Family

ID=65904618

Family Applications (1)

Application Number Title Priority Date Filing Date
CA3093802A Pending CA3093802A1 (en) 2018-03-13 2019-03-12 Substituted imidazopyridines as inhibitors of plasma kallikrein and uses thereof

Country Status (8)

Country Link
US (3) US10730874B2 (en)
EP (1) EP3765459A1 (en)
JP (2) JP2021517893A (en)
KR (1) KR20200143376A (en)
CN (1) CN112135825A (en)
AU (1) AU2019234670B2 (en)
CA (1) CA3093802A1 (en)
WO (1) WO2019178129A1 (en)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3070717A1 (en) * 2017-08-04 2019-02-07 Dyax Corp. Inhibitors of plasma kallikrein and uses thereof
WO2019178129A1 (en) 2018-03-13 2019-09-19 Shire Human Genetic Therapies, Inc. Substituted imidazopyridines as inhibitors of plasma kallikrein and uses thereof
JPWO2020204112A1 (en) 2019-04-01 2020-10-08
JP2022548696A (en) * 2019-09-18 2022-11-21 武田薬品工業株式会社 Plasma kallikrein inhibitors and uses thereof
JP2022549601A (en) * 2019-09-18 2022-11-28 武田薬品工業株式会社 heteroaryl plasma kallikrein inhibitors
WO2021211938A1 (en) 2020-04-17 2021-10-21 Shire Human Genetic Therapies, Inc. Solid forms of inhibitors of plasma kallikrein
US20230167132A1 (en) 2020-04-17 2023-06-01 Takeda Pharmaceutical Company Limited Forms and compositions of inhibitors of plasma kallikrein
JPWO2022071428A1 (en) 2020-09-30 2022-04-07
CN117355521A (en) 2021-03-17 2024-01-05 武田药品工业株式会社 Heteroaryl inhibitors of plasma kallikrein
EP4308564A1 (en) 2021-03-17 2024-01-24 Takeda Pharmaceutical Company Limited Polycyclic inhibitors of plasma kallikrein
WO2022197763A1 (en) 2021-03-17 2022-09-22 Shire Human Genetic Therapies, Inc. Inhibitors of plasma kallikrein
JP2024510503A (en) 2021-03-17 2024-03-07 武田薬品工業株式会社 Plasma kallikrein inhibitor
CN117396473A (en) 2021-03-17 2024-01-12 武田药品工业株式会社 Imidazopyridinyl inhibitors of plasma kallikrein
WO2024059186A1 (en) 2022-09-15 2024-03-21 Takeda Pharmaceutical Company Limited N-((isoquinolin-6-yl)methyl)-1h-pyrazole-4-carboxamid derivatives as plasma kallikrein inhibitors for the treatment of hereditary angioedema

Family Cites Families (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4911920A (en) 1986-07-30 1990-03-27 Alcon Laboratories, Inc. Sustained release, comfort formulation for glaucoma therapy
FR2588189B1 (en) 1985-10-03 1988-12-02 Merck Sharp & Dohme LIQUID-GEL PHASE TRANSITION PHARMACEUTICAL COMPOSITION
JPH0832707B2 (en) 1986-02-05 1996-03-29 富山化学工業株式会社 Novel cephalosporins and their salts
ATE141502T1 (en) 1991-01-15 1996-09-15 Alcon Lab Inc USE OF CARRAGEENAN IN TOPICAL OPHTHALMOLOGICAL COMPOSITIONS
US5212162A (en) 1991-03-27 1993-05-18 Alcon Laboratories, Inc. Use of combinations gelling polysaccharides and finely divided drug carrier substrates in topical ophthalmic compositions
DE69232557T2 (en) 1991-05-20 2002-10-24 Rhone Poulenc Rorer Internat H AROMATIC OLIGOMER COMPOUNDS AS IMITATORS BIOACTIVE MACROMOLECULES
US6309853B1 (en) 1994-08-17 2001-10-30 The Rockfeller University Modulators of body weight, corresponding nucleic acids and proteins, and diagnostic and therapeutic uses thereof
AU715658B2 (en) 1996-04-03 2000-02-10 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
JP2000256286A (en) 1999-03-11 2000-09-19 Kaken Pharmaceut Co Ltd Alkylamine derivative
AU2001273040A1 (en) 2000-06-27 2002-01-08 Du Pont Pharmaceuticals Company Factor xa inhibitors
EP1217000A1 (en) 2000-12-23 2002-06-26 Aventis Pharma Deutschland GmbH Inhibitors of factor Xa and factor VIIa
MY139563A (en) 2002-09-04 2009-10-30 Bristol Myers Squibb Co Heterocyclic aromatic compounds useful as growth hormone secretagogues
JP2007516192A (en) 2003-07-09 2007-06-21 パラダイム・セラピューティクス・リミテッド Organosilicon compounds and uses thereof
WO2005115382A1 (en) 2004-05-29 2005-12-08 7Tm Pharma A/S Crth2 receptor ligands for medicinal uses
WO2006091898A2 (en) 2005-02-25 2006-08-31 Adenosine Therapeutics, Llc Pyrazolyl substituted xanthines
WO2007009236A1 (en) 2005-07-20 2007-01-25 Merck Frosst Canada Ltd. Heteroaromatic compounds as inhibitors of stearoyl-coenzyme a delta-9 desaturase
EP1849781A1 (en) 2006-04-28 2007-10-31 Laboratorios del Dr. Esteve S.A. Substituted 3-Amino-4-hydroxy pyrrolidines compounds, their preparation and use as medicaments
EP1908471A1 (en) 2006-10-04 2008-04-09 Speedel Experimenta AG Tetrahydropyridines as renin inhibitors
EP1908762A2 (en) 2006-10-04 2008-04-09 Speedel Experimenta AG Organic compounds
US8153658B2 (en) 2006-11-16 2012-04-10 Astellas Pharma, Inc. Piperidine derivative or salt thereof
EP1974729A1 (en) 2007-03-28 2008-10-01 Santhera Pharmaceuticals (Schweiz) AG Substituted imidazopyridine derivates as melanocortin- 4 receptor antagonists
CA2934114A1 (en) 2007-06-12 2008-12-18 Achaogen, Inc. Antibacterial agents
BRPI0814939A2 (en) 2007-08-10 2015-01-27 Glaxosmithkline Llc CHEMICAL ENTITY, PHARMACEUTICAL COMPOSITION, AND METHOD FOR TREATING A VIRAL INFECTION IN A MAMMALIAN.
KR100994115B1 (en) 2008-08-18 2010-11-15 삼성모바일디스플레이주식회사 An organic light emitting diode employing a layer for improving a light efficiency
US20100160369A1 (en) 2008-12-04 2010-06-24 Exelixis, Inc. S1P1 Agonists and Methods of Making And Using
US20100204265A1 (en) 2009-02-09 2010-08-12 Genelabs Technologies, Inc. Certain Nitrogen Containing Bicyclic Chemical Entities for Treating Viral Infections
WO2010124082A1 (en) 2009-04-22 2010-10-28 Janssen Pharmaceutica Nv Azetidinyl diamides as monoacylglycerol lipase inhibitors
TW201109327A (en) 2009-05-28 2011-03-16 Otsuka Pharma Co Ltd Heterocyclic compound
US9394279B2 (en) 2009-06-11 2016-07-19 Abbvie Inc. Anti-viral compounds
US8937150B2 (en) 2009-06-11 2015-01-20 Abbvie Inc. Anti-viral compounds
GB201007187D0 (en) 2010-04-29 2010-06-09 Iti Scotland Ltd Ubiquitination modulators
WO2012016133A2 (en) 2010-07-29 2012-02-02 President And Fellows Of Harvard College Ros1 kinase inhibitors for the treatment of glioblastoma and other p53-deficient cancers
US9273028B2 (en) 2010-10-29 2016-03-01 Biogen Ma Inc. Heterocyclic tyrosine kinase inhibitors
JP2012111731A (en) 2010-11-26 2012-06-14 Otsuka Pharmaceut Co Ltd Medicine
KR101974665B1 (en) 2010-12-13 2019-05-02 어레이 바이오파마 인크. SUBSTITUTED N-(1H-INDAZOL-4-YL)IMIDAZO[1,2-a]PYRIDINE-3-CARBOXAMIDE COMPOUNDS AS TYPE III RECEPTOR TYROSINE KINASE INHIBITORS
US8883793B2 (en) 2010-12-29 2014-11-11 Development Center For Biotechnology Tubulin inhibitors and methods of using the same
US9464065B2 (en) 2011-03-24 2016-10-11 The Scripps Research Institute Compounds and methods for inducing chondrogenesis
RU2013150349A (en) 2011-04-13 2015-05-20 Мерк Шарп И Доум Корп. 5-SUBSTITUTED IMINOTIAZINES AND THEIR MONO- AND DIOXIDES AS YOUR INHIBITORS CONTAINING THEIR COMPOSITIONS AND THEIR APPLICATION
GB2494851A (en) 2011-07-07 2013-03-27 Kalvista Pharmaceuticals Ltd Plasma kallikrein inhibitors
JPWO2013081094A1 (en) 2011-11-30 2015-04-27 東レ株式会社 Imidazo [1,2-a] pyridine derivative and its pharmaceutical use
US9617268B2 (en) 2011-12-30 2017-04-11 Ptc Therapeutics, Inc. Compounds for treating spinal muscular atrophy
LT2820008T (en) 2012-03-02 2017-06-12 Genentech, Inc. Amido spirocyclic amide and sulfonamide derivatives
AR096393A1 (en) 2013-05-23 2015-12-30 Bayer Cropscience Ag PESTICIDE HETEROCYCLIC COMPOUNDS
RU2674028C2 (en) 2013-08-14 2018-12-04 Калвиста Фармасьютикалз Лимитед Enzyme inhibitors
US9765070B2 (en) 2013-10-30 2017-09-19 Bayer Pharma Aktiengesellschaft Substituted oxopyridine derivatives
WO2015095449A1 (en) 2013-12-19 2015-06-25 Ptc Therapeutics, Inc. Methods for modulating the amount rna transcripts
EP3087067B1 (en) 2013-12-26 2018-10-24 Takeda Pharmaceutical Company Limited 4-(piperrazin-1-yl)-pyrrolidin-2-one compounds as monoacylglycerol lipase (magl) inhibitors
US9611252B2 (en) 2013-12-30 2017-04-04 Lifesci Pharmaceuticals, Inc. Therapeutic inhibitory compounds
JP6759100B2 (en) 2013-12-30 2020-09-23 ライフサイ ファーマシューティカルズ，インク． Therapeutic inhibitor compound
WO2015188051A1 (en) 2014-06-06 2015-12-10 Biogen Ma Inc. Atx modulating agents
JP6951970B2 (en) * 2014-07-16 2021-10-20 ライフサイ ファーマシューティカルズ，インク． Therapeutic inhibitor compound
US10913736B2 (en) 2014-08-22 2021-02-09 University Of Washington Specific inhibitors of methionyl-tRNA synthetase
GB201421088D0 (en) 2014-11-27 2015-01-14 Kalvista Pharmaceuticals Ltd New enzyme inhibitors
GB201421083D0 (en) 2014-11-27 2015-01-14 Kalvista Pharmaceuticals Ltd Enzyme inhibitors
GB201421085D0 (en) 2014-11-27 2015-01-14 Kalvista Pharmaceuticals Ltd New enzyme inhibitors
CN105777632A (en) 2015-01-09 2016-07-20 成都贝斯凯瑞生物科技有限公司 Aromatic-ring azacyclo derivatives and application thereof
WO2017001926A2 (en) 2015-07-01 2017-01-05 Lifesci Pharmaceuticals, Inc Therapeutic inhibitory compounds
US20190263818A1 (en) 2015-07-01 2019-08-29 Lifesci Pharmaceuticals, Inc. Therapeutic inhibitory compounds
AU2016367261A1 (en) 2015-12-11 2018-07-26 Lifesci Pharmaceuticals, Inc. Therapeutic inhibitory compounds
HUE061989T2 (en) 2016-03-16 2023-09-28 Kura Oncology Inc Substituted thieno[2,3-d]pyrimidine derivatives as inhibitors of menin-mll and methods of use
GB201609519D0 (en) 2016-05-31 2016-07-13 Kalvista Pharmaceuticals Ltd Polymorphs of n-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyr idin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide
IL293304A (en) 2016-05-31 2022-07-01 Kalvista Pharmaceuticals Ltd Pyrazole derivatives as plasma kallikrein inhibitors
GB201609607D0 (en) 2016-06-01 2016-07-13 Kalvista Pharmaceuticals Ltd Polymorphs of N-(3-Fluoro-4-methoxypyridin-2-yl)methyl)-3-(methoxymethyl)-1-({4-((2-oxopy ridin-1-yl)methyl)phenyl}methyl)pyrazole-4-carboxamide and salts
GB201609603D0 (en) 2016-06-01 2016-07-13 Kalvista Pharmaceuticals Ltd Polymorphs of N-[(6-cyano-2-fluoro-3-methoxyphenyl)Methyl]-3-(methoxymethyl)-1-({4-[(2-ox opyridin-1-YL)Methyl]phenyl}methyl)pyrazole-4-carboxamide
EP3481391A4 (en) * 2016-07-11 2020-03-11 Lifesci Pharmaceuticals, Inc. Therapeutic inhibitory compounds
WO2018015818A2 (en) 2016-07-15 2018-01-25 Lifesci Pharmaceuticals, Inc. Therapeutic inhibitory compounds
US10280172B2 (en) * 2016-09-29 2019-05-07 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
CN110418789B (en) 2017-02-01 2022-03-25 常州千红生化制药股份有限公司 Derivatives of N-cycloalkyl/heterocycloalkyl-4- (imidazo [1,2-a ] pyridine) pyrimidin-2-amines as therapeutic agents
WO2018161033A1 (en) 2017-03-02 2018-09-07 Wright, Adrian Small molecule ire1-alpha inhibitors
WO2018229543A2 (en) 2017-06-14 2018-12-20 Lifesci Pharmaceuticals, Inc. Therapeutic inhibitory compounds
BR112019027127A2 (en) 2017-06-22 2020-07-07 Curadev Pharma Limited small molecule human sting modulators
CA3070717A1 (en) 2017-08-04 2019-02-07 Dyax Corp. Inhibitors of plasma kallikrein and uses thereof
GB201719882D0 (en) 2017-11-29 2018-01-10 Kalvista Pharmaceuticals Ltd Solid forms of a plasma kallikrein inhibitor and salts thereof
GB201719881D0 (en) 2017-11-29 2018-01-10 Kalvista Pharmaceuticals Ltd Solid forms of plasma kallikrein inhibitor and salts thereof
WO2019178129A1 (en) 2018-03-13 2019-09-19 Shire Human Genetic Therapies, Inc. Substituted imidazopyridines as inhibitors of plasma kallikrein and uses thereof
JP2022548696A (en) 2019-09-18 2022-11-21 武田薬品工業株式会社 Plasma kallikrein inhibitors and uses thereof
JP2022549601A (en) 2019-09-18 2022-11-28 武田薬品工業株式会社 heteroaryl plasma kallikrein inhibitors

Also Published As

Publication number Publication date
US10730874B2 (en) 2020-08-04
TW202003513A (en) 2020-01-16
KR20200143376A (en) 2020-12-23
WO2019178129A1 (en) 2019-09-19
JP2021517893A (en) 2021-07-29
US20230078513A1 (en) 2023-03-16
CN112135825A (en) 2020-12-25
US11352356B2 (en) 2022-06-07
JP2024012697A (en) 2024-01-30
EP3765459A1 (en) 2021-01-20
US20200317667A1 (en) 2020-10-08
AU2019234670B2 (en) 2023-11-23
AU2019234670A1 (en) 2020-09-03
US20190284182A1 (en) 2019-09-19

Similar Documents

Publication Publication Date Title
CA3093802A1 (en) Substituted imidazopyridines as inhibitors of plasma kallikrein and uses thereof
CA2930414C (en) Tetrahydroquinoline compositions as bet bromodomain inhibitors
CN102131807B (en) Pyrazolopyridine kinase inhibitors
US11787796B2 (en) Plasma Kallikrein inhibitors and uses thereof
KR20170066566A (en) Heteroaryl compounds as btk inhibitors and uses thereof
CA2935867A1 (en) Heteroaryls and uses thereof
CZ20031028A3 (en) Aza- and polyazanaphthalenyl carboxamides
MX2014011373A (en) Diacylglycerol acyltransferase 2 inhibitors.
US11370803B2 (en) Heteroaryl plasma kallikrein inhibitors
AU2014302710B2 (en) Imidazole compounds as modulators of FSHR and uses thereof
EP4308227A1 (en) Imidazopyridinyl inhibitors of plasma kallikrein
CN117396469A (en) Inhibitors of plasma kallikrein
EP4308564A1 (en) Polycyclic inhibitors of plasma kallikrein
TWI834641B (en) Inhibitors of plasma kallikrein and uses thereof
TW201231467A (en) Pyrazolopyridine kinase inhibitors
OA17143A (en) Diacylglycerol acyltransferase 2 inhibitors
CA2651420A1 (en) Spiro tetracyclic compound

Legal Events

Date Code Title Description
EEER Examination request

Effective date: 20240311